The Ethical Challenges of the Stem Cell Revolution 1527555879, 9781527555877

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Copyright © 2020. Cambridge Scholars Publisher. All rights reserved.

The Ethical Challenges of the Stem Cell Revolution

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

Copyright © 2020. Cambridge Scholars Publisher. All rights reserved. Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

The Ethical Challenges of the Stem Cell Revolution By

Copyright © 2020. Cambridge Scholars Publisher. All rights reserved.

Audrey R. Chapman

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

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.

Copyright © 2020. Cambridge Scholars Publisher. All rights reserved.

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

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

Copyright © 2020. Cambridge Scholars Publisher. All rights reserved.

To my husband Karim

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

Copyright © 2020. Cambridge Scholars Publisher. All rights reserved. Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

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

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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 Cell Therapy and Access to its Benefits

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

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ACKNOWLEDGEMENTS

This book results from my 20 years of involvement with and reflections on human 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 Medical Ethics 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 postdoctoral 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.

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

CHAPTER ONE

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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 adult stem cell, hematopoietic stem cells harvested from bone marrow, to try to treat patients with blood 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 humans 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 embryonic stem cell 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.

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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

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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 gene therapy 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

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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 embryo (technically a blastocyst), 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 the New York Times, Shinya Yamanaka, 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 embryos 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

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Introduction and Overview

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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

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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

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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 primitive streak 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

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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

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Introduction and Overview

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the human embryo is owed protection from the time of fertilization. When representatives of this tradition were contacted by the Singapore Bioethics 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

Chapman, Audrey R.. The Ethical Challenges of the Stem Cell Revolution, Cambridge Scholars Publisher, 2020. ProQuest

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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.

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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

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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

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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 abortion 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 Bill Clinton 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

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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

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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

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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 Barack Obama 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

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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 clone 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

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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.

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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.

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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.

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Introduction and Overview

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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

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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.

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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.

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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-billiondollar-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-donorsdifficult-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.

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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-stemcells.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

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Pluripotent Stem Cells from Cultured Human Primordial Germ Cells.” Proceedings of the National Academy of Sciences 95 (23): 13726–31. Takahashi, Kazutoshi, Koji Tanabe, Mari Ohnuki, Megumi Narita, Tomoko Ichisaka, Kiichiro Tomoda, and Shinya Yamanaka (2007) “Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors.” Cell 131 (5): 861–72. Thomson, James A., Joseph Itskovitz-Eldor, Sander S. Shapiro, Michelle A. Waknitz, Jennifer J. Swiergiel, Vivienne S. Marshall, and Jeffrey M. Jones (1998) “Embryonic Stem Cell Lines Derived from Human Blastocysts.” Science 282 (5391): 1145–7. Vatican Congregation for the Doctrine of the Faith (1987) “Donum Vitae. Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation.” Origins 16: 697–711. Vogel, Gretchen (1999) “Capturing the Promise of Youth.” Science 286 (5448): 2238–9. Wadman, Meredith (2013) “High Court Ensured Continued US Funding of Human Embryonic-Stem-Cell Research.” Nature, January. https://doi.org/10.1038/nature.2013.12171. Walters, LeRoy (2004) “Human Embryonic Stem Cell Research: An Intercultural Perspective.” Kennedy Institute of Ethics Journal 14 (1): 3–38. Zoloth, Laurie (2001) “The Ethics of the Eighth Day: Jewish Bioethics and Research on 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, 95–111. Cambridge, MA: MIT Press.

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CHAPTER TWO

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THE ETHICS OF STEM CELL CHOICE

The choice of the stem cell type – human embryonic stem cells, human induced pluripotent stem cells, or human multipotent adult stem cells – for research and the development of therapies has significant ethical as well as scientific implications. The type of cell and the source from which it is derived constitute one set of ethical issues. 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. As noted in Chapter One, some ethicists and religious thinkers, particularly those from the Roman Catholic tradition and conservative Protestant denominations, consider the embryo, even a week-old, 200-cell blastocyst the size of a pinhead, to have full human status and therefore to be entitled to the same protections accorded to a person after birth. They have therefore opposed human embryonic stem cell research because it entails the destruction of preimplantation embryos. Other ethicists and religious thinkers, as well as scientists, do not consider the derivation of and research with human embryonic stem cells to be ethically problematic. Rather, they argue that using surplus embryos for the development of therapies to relieve human suffering is a moral priority. Moreover, among those subscribing to an embryo protection framework, there are disagreements as to whether researchers working with human embryonic stem cells, but not deriving new lines, are complicit in embryo destruction. This chapter will evaluate these issues and their implications. Further complicating this ethical analysis, human embryonic stem cell lines can be generated without embryo destruction by removing single cells from a blastomere (preserving the embryo) by using micromanipulation techniques similar to those used in preimplantation genetic diagnosis (Klimanskaya et al. 2006). Another alternative is to develop embryonic stem cell lines from parthenotes produced from unfertilized ova that are incapable of developing beyond an early embryonic stage (Daughtry and Mitalipov 2014). However, these approaches have been little used, possibly because the U.S. National Institutes of Health (NIH) has not made them eligible for

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use with federal grants, and therefore they have not been part of the ethical discussion of the choice of stem cell type to date. The potential of the type of stem cell for developing medical therapies and regenerative medicine constitutes a second ethical issue this chapter will consider. Not all types of pluripotent or multipotent cells are equally suitable for clinical applications. For those in favor of developing and using pluripotent stem cells for therapeutic purposes, the selection of the type of stem cell best able to give rise to safe and effective medical therapies is an ethical issue of at least equal importance as the source of the cell. Here the ethical focus is on the potential beneficiaries and the capacity of the stem cells to improve human health and welfare rather than on the status of the embryo. This chapter will also explore this issue. To assess the ethics of stem cell choice, both sets of ethical issues need to be evaluated. For example, while adult or somatic stem cells do not raise ethical issues other than ensuring that informed consent is received from the donor of the tissue from which the cells are derived, most adult stem cells have limited utility for the development of a wide range of medical therapies. Additionally, the more than one thousand clinical trials of candidate therapies derived from adult stem cells, particularly mesenchymal stem cells, for the most part have had disappointing results. And lest anyone assume all of this is solely theoretical, I would like to emphasize that the interaction between these ethical issues has had a major impact on the development of the pluripotent stem cell field. In a 2017 article, Jordan Poulos proposed that the reason that major breakthroughs in stem cell research had not yet enjoyed clinical success derived from the polarizing effect of the ethical debate around their use. “The intractability of the ethical debate is double edged: legislators not only have placed tighter restrictions on certain stem cell therapies, but do so in favour of less controversial cells which will have worse outcomes for patients” (Poulos 2018, 1). I would qualify this statement, in that there has been some clinical success in early-stage trials with induced pluripotent stem cells. However, as this book will show, work with human embryonic stem cells, widely accepted as the gold standard for pluripotent stem cell research and more appropriate for clinical applications, has definitely encountered multiple types of roadblocks.

Ethical Issues in Choice of the Pluripotent Cell Type Several ethical and theological assumptions define those who believe that the embryo at the blastocyst stage, located outside a mother’s body requires protection from destruction by researchers. The most fundamental is that

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human dignity is fully established at conception whether the conceptus is within or outside the mother’s body. As Ted Peters explains this position, “What makes a human being a person is origin. Our origin at conception establishes our individuality, our dignity, and our moral protectibility” (Peters 2007, 31). What is important to this position is genomic novelty. According to Pope John Paul II, when the sperm and egg unite to create a unique genome, God implants an immortal spiritual soul in the conceptus. It is this spiritual soul that then imparts dignity, a dignity that must always be protected (Peters 2007, 31). Therefore, those adhering to the embryo protection position believe that our first ethical responsibility is to do no harm to the embryo, even if it is at the expense of thwarting medical advances (Peters 2007, 33). The use of surplus embryos leftover from fertility treatments or discarded embryos not of sufficient quality to implant is also perceived as illicit because the intentional destruction of innocent human life at any stage is inherently evil (Peters 2007, 37). However, science complicates and contradicts these theological assumptions. Conception is not a single moment when a new, individual person is created. Scientific research indicates that embryogenesis is a process that takes place over several days. Moreover, each new human being does not necessarily possess a unique genome. After conception, each cell is totipotent for several days and capable of making multiple new persons, as they do when the conceptus divides into twins, triplets, or quadruplets sharing the same genome. Individuation, the development of a single human being, occurs only after specialized cells and membranes appear about 14 days after fertilization. This means that it would be possible to affirm the dignity of the embryo by prohibiting its destruction after individuation and still support embryonic stem cell research (Peters 2007, 45–46). Another assumption of the embryo protection position is that the early embryo should not be harmed or destroyed because it has the potential to develop into a person, and that this potentiality warrants protection. However, bioethicists and philosophers have identified a weakness in the potentiality argument. As Katrien Devolder points out, “acorns are not oak trees, nor are eggs chickens or omelettes. Just because something has the potential to become something different, we should not regard it as if it has already realised that potential” (Devolder 2009, 1285). According to Insoo Hyun, the weakness of all secular and religious potentiality arguments is that they ignore the crucial requirement that human embryos in vitro must be implanted in a woman’s uterus for embryonic development to continue past the first few days after they have been created. He argues that, therefore, embryo protectionists who insist that ex vivo embryos have a

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right to live based on their potential must also insist that this right creates a corresponding moral duty for women to accept implantation and gestation to term (Hyun 2013, 29), a position they have not taken as yet. Many opponents of human embryonic stem cell research are motivated by a desire not to be morally complicit in the destruction of human embryos. Complicity refers to being associated in some way with another’s wrongdoing. Moral complicity theory, particularly as articulated by those working within the Roman Catholic tradition, holds that, under certain conditions, those who participate in an activity that is morally evil, even if indirectly, are themselves morally responsible. In this theory, cooperation with evil can be of two kinds. The first type, “formal” cooperation, involves both intending to participate in the wrongdoing of another and actively doing so. In contrast, “material” cooperation occurs when someone contributes to the wrongdoing without intending to do so. There are two forms of such material cooperation or complicity. It can be “immediate” or it can be “mediate.” In the former case, the person acting is directly involved in the wrongdoing; in the latter, the person contributes to the wrongdoing of another either at the time of the original act or afterwards (Brown 2009, 12). Material complicity is considered to be culpable if the acts of the participant are the foreseeable proximate cause of a morally wrong outcome, even if remote. Also, according to Roman Catholic moral theology, the good of saving lives cannot outweigh the evil of killing an innocent human being, even if that innocent being is a three-day-old preimplantation embryo. Many of those committed to protecting early preimplantation embryos oppose embryonic stem cell research even when it uses existing lines derived by other researchers, because they perceive a chain of complicity. For example, Richard Doerflinger, a spokesperson for the U.S. Catholic Conference of Bishops, claims that researchers who use the embryonic cell lines are necessarily complicit in the destruction of the embryo. His reasoning is that the harvesting of embryonic stem cells and research with these cells are components of the same enterprise since the research presupposes the harvesting and that it will be performed in specified ways (Doerflinger 1999, 141). Along with disputing the premise that early preimplantation embryos deserve protection, analysts have questioned Doerflinger’s assumption that the harvesting of embryonic stem cells and research with those cells are components of the same act (Curzer 2004, 539–40). President Clinton’s National Bioethics Advisory Commission, for example, concluded that “the processes of derivation and use are sufficiently different to warrant being regarded as morally distinct from one another” (1999, 54). It has also been pointed out that “people do

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not become complicit in a wrong merely by benefiting from it; they must actually participate in, encourage, endorse, tolerate, or hinder the healing of the wrong” (Curzer 2004, 541). Some others opposing human embryonic stem cell research are concerned that successes from this research could create further demand and thereby promote further embryo destruction to generate additional lines. In response, some human embryonic stem cell research supporters point out that more than a sufficient number of embryonic stem cell lines have been created, enough to meet the need of researchers. By 2016, at least 2,168 different human embryonic stem cell lines were publicly known (Guhr et al. 2018, 5). Moreover, embryos will continue to be discarded on a large scale from in vitro fertilization for fertility treatments, regardless of whether human embryonic stem cell research continues (Devolder 2010). Interestingly, opponents of human embryonic stem cell research have rarely addressed the fertility treatment practices that have resulted in the creation of perhaps up to a million surplus embryos now stored in freezers. Many of the opponents of human embryonic stem cell research assume that human induced pluripotent stem cell research avoids the pitfalls of moral complicity in the destruction of early human life. But does it? The philosopher Mark Brown claims it does not. Brown argues that the close relationship between human embryonic stem cell research and induced pluripotent stem cell research means that human induced pluripotent stem cell researchers, like scientists working with human embryonic stem cells, are morally complicit in the destruction of a form of human life. “Induced pluripotent stem cell technology originated in human embryonic stem cell research, subsequent advances in the field depended directly or indirectly upon human embryonic stem cell research and major elements of the [induced pluripotent stem cell] research agenda are methodologically committed to the intensive study of pluripotency as it is expressed in the human embryo” (Brown 2009, 12). Brown cautions that technological advances rarely bypass foundational ethical questions. More often, as in the case of induced pluripotent stem cell research, the ethical problem is reframed in a different context. More specifically, he reasons that induced pluripotent stem cell researchers may avoid proximate material complicity, but not remote material complicity in embryo destruction. According to Brown, projected biomedical applications of induced pluripotent stem cells almost certainly will require more human embryonic stem cell research, and those who support induced pluripotent stem cell research would be morally complicit, formally and materially, in the embryo destruction necessary to evaluate and validate the development of these therapies. Additionally, he argues that

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publications that report upon induced pluripotent stem cell successes contribute directly to the pool of knowledge relevant to human embryonic stem cell researchers and indirectly to the financial resources available for human embryonic stem cell research. He points out that support for induced pluripotent stem cell research will likely stimulate aggregate demand for other forms of stem cell research. He also cautions that advocacy for public policies that privilege induced pluripotent stem cell research could contribute to foregoing medical benefits for some groups of people with terminal diseases who might otherwise have been saved had there been more investments in human embryonic stem cell research. Since this outcome would be a foreseeable implication of such a policy preference, it would implicate induced pluripotent stem cell proponents in preventable harms to these patients. The debate on the moral propriety of conducting embryonic stem cell research, like the debate on abortion, is unlikely to be resolved because there is no clear compromise position. President Clinton’s National Bioethics Advisory Commission tried to scope out an intermediary position on this issue that recognized the embryo as an early form of human life. It identified the following as a reasonable statement of the kind of agreement that could be possible on this issue: Research that involves the destruction of embryos remaining after infertility treatments is permissible when there is good reason to believe that this destruction is necessary to develop cures for life-threatening or severely debilitating disease and when appropriate protections and oversight are in place in order to prevent abuse (National Bioethics Advisory Commission 1999, 52).

However, those holding an embryo protection position do not agree with the assessment that the potential benefits of the research outweigh the harms to the embryos that are destroyed in the research process.

Can Induced Pluripotent Stem Cells Serve as a Replacement for Embryonic Stem Cells? When human induced pluripotent stem cells were initially developed, many opponents of human embryonic stem cell research claimed that these stem cells would offer the same scientific capabilities as human embryonic stem cell research without raising the ethical and theological issues related to the destruction of early preimplantation embryos. The availability of an alternative form of pluripotent cells prompted those for whom embryo

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protection was a priority to argue that human embryonic stem cell research was no longer necessary. For example, the columnist Charles Krauthammer, then a member of President George W. Bush’s Council on Bioethics, claimed, “the embryonic stem cell debate is over…Scientific reasons alone will now incline even the most willful researchers to leave the human embryo alone” (cited in Holden and Vogel 2008). This reasoning assumes that induced pluripotent stem cells are fully equivalent to human embryonic stem cells, but scientific evidence does not support this assessment. While initial reports demonstrated the overall similarities between induced pluripotent stem cells and embryonic stem cells, more recent studies have identified genomic and epigenetic differences between the two types of pluripotent cells. More refined analyses of how induced pluripotent stem cells behave in vitro, along with genome-wide genetic and epigenetic analyses, have revealed numerous subtle but substantial molecular differences (Robinton and Daley 2012, 295). Studies have found differential methylation patterns between induced pluripotent stem cells and embryonic stem cells as well as between types of induced pluripotent stem cells (Doi et al. 2009). When Raman spectroscopy, an instrument that provides a structural fingerprint by which molecules can be identified, was used to perform a comparative analysis of the two types of pluripotent stem cells, small but significant differences were detected, particularly with regard to their nucleic acid levels (Parrotta et al. 2017). Induced pluripotent stem cells and embryonic stem cells also were shown to have different gene expression signatures (Chin et al. 2009). These include subtle differences in the expression of messenger RNAs and of micro RNAs (Narsinh, Plews, and Wu 2011, 635). In addition, analyses show variability in the in vitro differentiation potential of human induced pluripotent stem cells as compared with human embryonic stem cells. Some research has indicated that human embryonic stem cells have a much higher rate of differentiation into specialized cell types and less variation in their ability to differentiate (Hu et al. 2010). For example, researchers have observed a reduced and more variable yield of neural and cardiovascular progeny with human induced pluripotent stem cells than with human embryonic stem cells (Narsinh, Plews, and Wu 2011, 635). The functional implications of these differences are unclear. Until they are determined, human embryonic stem cells will be the safer alternative for clinical applications. Moreover, stem cell scientists have argued that it would be a serious mistake to assume that induced pluripotent research eliminates the need for work with human embryonic stem cells. There is a general scientific consensus that human embryonic stem cell research remains the

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“gold standard” of pluripotent stem cell research against which researchers can compare induced pluripotent stem cells. Indeed, scientists use embryonic stem cells to understand pluripotency (Cyranoski 2018, 429). In 2007, four leaders in the stem cell field, one of whom was Shinya Yamanaka, the scientist who discovered induced pluripotent stem cells, cautioned, “the recent advances in [induced pluripotent stem] cell research would not be possible if it were not for the many years of dedicated [human embryonic stem cell] research that preceded them. We cannot support the notion that [induced pluripotent stem] cell research can advance without [human embryonic stem cell] research” (Hyun et al. 2007, 367–68). Recently, Yamanaka commented, “The importance of human [embryonic stem] cells is no less now than 20 years ago, and I do not imagine it will be any lower in the future” (quoted in Cyranoski 2018, 430).

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Potential of Adult Stem Cells for Clinical Applications Adult stem cells, also known as somatic stem cells, are undifferentiated cells found throughout the body that replenish dying cells and repair damaged tissue. An adult stem cell can differentiate to yield some or all of the major specialized cell types in the tissue or organ in which it is located. A few types of multipotent adult stem cells can also transdifferentiate into some cell types different than those found in the organs or tissues in which they are located. Adult stem cells do not raise special ethical concerns beyond having informed consent for the donation of the tissue from which they are derived and for any human research or clinical applications for which they are used. They are widely used in research and clinical care, but they lack the indefinite growth capacity and plasticity of pluripotent stem cells. Also, unlike human embryonic stem cells, aging in culture has been shown to significantly reduce the survival and differentiation potential of some types of adult stem cells. Mesenchymal stem cells, adult stem cells found in the bone marrow, umbilical cord tissue, and fat, have been a particular focus of attention of researchers. Mesenchymal stem cells are multipotent, able to differentiate to form cartilage, bone, and fat. These cells are being tested in trials for orthopedic applications and for a wide range of other clinical indications. There are currently some 1,000 clinical trials with mesenchymal stem cells registered at ClinicalTrials.gov (Andrzejewska, Lukomska, and Janowski 2019). An earlier survey found that the immune system was the most common target of trials with mesenchymal stem cell therapies for various disease indications. Mesenchymal stem cells derived from bone marrow or adipose tissues were the predominant stem cell used

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in these applications. Trials of mesenchymal stem cells that examined their regenerative or reparative potential included Phase II trials for diabetes, pulmonary hypertension, and chronic obstructive pulmonary disease. Mesenchymal stem cells were also being tested for autoimmune diseases such as Crohn’s disease, multiple sclerosis, and diabetes, but the nonscientific manner in which many of the trials were being conducted made it difficult to evaluate their efficacy. Also, at least one prominent stem cell scientist, George Daley, has raised concerns over the expansion of mesenchymal stem cell trials into “indications where the clinical hypotheses are more speculative, the therapeutic mechanisms are incompletely defined, and in some instances the preclinical evidence highly contentious” (Daley 2012). The results of various of these trials have been disappointing. Although decades of laboratory research and animal testing have shown the safety and efficacy of therapies using these adult stem cells, when transplanted into patients the mesenchymal cells have been safe but lacking efficacy (Borlongan 2019). Poor engraftment and the low survival rate of the mesenchymal stem cells in the organ receiving the transplant are among the main problems. Some researchers have speculated that using CRISPR/Cas9 gene editing technology could enhance the therapeutic benefit these cells demonstrate in vivo (Filho et al. 2019). As will be discussed in Chapter Five, many of the clinical trials that the California Institute for Regenerative Medicine has funded use adult stem cells derived from patients and donors for a variety of types of applications. In fact, this is the case for the majority of the initial 60 clinical trials it sponsored. Hematopoietic and mesenchymal stem cells are the two most common types of adult stem cells in these trials. In several of the trials these cells have been modified using CAR T Therapies in which the patient’s own T cells have been genetically engineered outside of their bodies and then applied therapeutically (Chapman 2019). Nevertheless, after more than 60 years of research and thousands of clinical trials with adult stem cells, the only adult stem cell–based products that the U.S. Food and Drug Administration had approved for use in the United States as of 2018 were Hemacord, Clevecord, Allocord, and Ducord, all cord blood derivatives (Bioinformant 2018). No therapy based on mesenchymal stem cells has as yet won approval from the FDA. Proschymal, a mesenchymal stem cell therapy for juvenile acute graftversus-host disease, has received market authorization from Health Canada (Expert Advisory Panel on Prochymal 2012). Following a recommendation for approval by the European Medicines Agency, the European Commission has given conditional marketing authorization to the Holoclar system, which

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uses autologous corneal epithelial stem cells to repair limbal stem cells located in the eye that function to heal damage to the outer layer of the cornea (European Medicines Authority 2015). Also in 2018 the European Commission approved a drug containing mesenchymal stem cells for the treatment of enterocutaneous fistula arising from Crohn’s Disease (Filho et al. 2019, 470).

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Potential Advantages of the Use of Induced Pluripotent Stem Cells In addition to averting the need to destroy embryos to derive pluripotent stem cell lines, induced pluripotent stem cells offer other advantages. Many scientists find it easier to develop and work with human induced pluripotent stem cells than with human embryonic stem cells. It has been claimed that “Almost any competent cell biologist or geneticist can attempt to produce human [induced pluripotent stem] cells” (Hyun 2008, 21). Induced pluripotent stem cells provide an opportunity to derive pluripotent cells from patients suffering from a wide range of diseases and then to use them to create in vitro models to study the pathophysiology of the earliest stages of these disorders. It should be noted that, in recent years, scientists have also derived human embryonic stem cell disease lines from embryos with genetic disorders identified through prenatal genetic diagnosis and employed them for the same purpose (Guhr et al. 2018, 9). However, human induced pluripotent stem cells offer disease models for a greater range of genetic diseases. Induced pluripotent stem cells also offer enhanced platforms for drug discovery. The ability to generate quantities of disease-relevant tissues from patients suffering from many kinds of genetic diseases has facilitated the identification and screening of novel therapeutics. However, the persistence of the identity in derived tissue and the background genetic variability of induced pluripotent stem cell lines constitute barriers to further advancement of disease modeling. More complex differentiation systems are also being developed to more faithfully recapitulate human tissue- and organ-level dysfunction through the development of 3D organoids from induced pluripotent stem cells. Organoids are clusters of cells derived from pluripotent stem cells and grown in vitro that resemble miniature organs. Pluripotent stem cells are amenable to organoid-based studies as they have the capability of selforganization into the architecture of a wide variety of organs. (Rowe and Daley 2019; Elitt, Barbar, and Tesar 2018).

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Working with induced pluripotent stem cells also enables researchers to avoid time-consuming bureaucratic and regulatory procedures associated with human embryonic stem cell research. To obtain existing human embryonic stem cell lines researchers have to acquire a material transfer agreement (MTA) from the Wisconsin Alumnae Research Foundation, the holder of a patent on human embryonic stem cell lines. (Induced pluripotent stem cell lines that scientists derive themselves do not require completion of an MTA.) Following the recommendations of the National Academy of Sciences Human Embryonic Stem Cell Committee (2005), which in several states have been codified into law, many institutions have instituted specialized review and oversight processes for research involving human embryonic stem cells. Although the National Academy of Sciences had proposed undertaking similar oversight of induced pluripotent stem cell research, few institutions have adopted comparably stringent oversight procedures (Chapman 2015, 12). One of the sources of excitement with the discovery of induced pluripotent stem cells was the belief that this technology offers the possibility of developing cellular replacement therapies derived from a patient’s own cells. Doing so would be a major contribution to personalized medicine. It was also assumed that using a patient’s own cells would eliminate the need to use immune suppressants on an ongoing basis. However, problems that arose during the first human transplantation of an autologous pluripotent stem cell product, which took place at the RIKEN Institute in Japan in 2014, raised questions about the feasibility of this approach. The clinical trial involved the transplantation of a sheet of retinal pigment epithelium cells generated from induced pluripotent stem cells for the treatment of age-related macular degeneration. The trial went well with the first treated patient. She reportedly did not suffer any serious adverse effects and her visual acuity stabilized following the treatment. But the safety testing of the second patient’s induced pluripotent stem cells revealed several mutations in the genetic sequence that did not exist in the patient’s original fibroblasts. These genetic changes have been documented as frequently occurring in the induced pluripotent stem cell reprogramming process, and problematically, one of the singlenucleotide variations has been identified as a somatic cancer-associated mutation (Blair and Barker 2016, 423). The investigators at RIKEN decided to change strategy and proceed with partially matched allogeneic cells instead of the patient’s own cells (Garber 2015, 891). The RIKEN trial also identified other challenges for developing an autologous therapy. Researchers found that the quality and safety of each induced pluripotent stem cell line is variable. They had to generate 30 lines

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in order to select a satisfactory line for the first patient. The cost of doing so was prohibitive. It is estimated that the cost per patient for the development of autologous induced pluripotent stem cell lines using this approach would be US $1,000,000. In addition to the cost, it is difficult to envision how to develop the capacity needed to generate personalized therapies to serve the population with potential disorders needing treatment. The problems with autologous transplantation faced by the RIKEN group have discouraged many scientists from proceeding with this approach as viable for clinical therapy, at least in the short to medium term (Blair and Barker 2016, 425). There are other obstacles to autologous transplantation. It has been assumed that autologous induced pluripotent stem cells would be immunetolerated by the recipient from whom the cells are derived, but this is not always the case. Research has shown that abnormal gene expression in some cells differentiated from induced pluripotent stem cells can induce an immune response in recipients, making it advisable to evaluate the immunogenicity of cells derived from patient-specific induced pluripotent stem cells before any clinical application of these autologous cells into the patients (Zhao et al. 2011). Subsequent research has shown that de novo mutations in mitochondrial DNA induced by cell reprogramming or rare mutations already present may trigger an immune response that makes induced pluripotent stem cells likely to be rejected when transplanted (Deuse et al. 2019). In patients with genetic diseases, it would be problematic to transplant tissue with the mutation that caused the disease in the first place. Although the mutation might be corrected, for example by using gene splicing technology, doing so would be time consuming, expensive, and subject to additional regulatory scrutiny. This would open patients with complex genetic disorders to further uncertainty (Blair and Barker 2016, 424). To address these issues, the creation of induced pluripotent stem cell haplobanks has been proposed. The idea is to provide an established source of clinical grade pluripotent stem cells from selected homozygous human leukocyte antigen (HLA)–typed donors that could provide HLAmatched cells to at least some patients’ major leukocyte antigens, a key determinant of transplant rejection. Doing so would be more feasible for relatively homogenous populations. It has been estimated, for example, that induced pluripotent stem cell lines from 140 HLA homozygotes would cover up to 90 percent of the Japanese population. A project to do so is underway and completion is anticipated in 2023 (Garber 2015). More genetically diverse populations would require far more cell types. Moreover, the proposal to use induced pluripotent stem cell haplobanks is fraught with uncertainty. It cannot be assumed that a specific

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cell type needed for therapy can be generated from a single banked cell line, and there is no current method for determining the potential of a cell prospectively. To achieve coverage of the population with a relatively small number of cell lines will require acceptance of an imperfect match at up to two HLA loci, likely resulting in the need for immunosuppression. The failure to match blood types could also lead to rejection. In countries with a great deal of ethnic diversity, it is unlikely that members of all groups could be matched (Blair and Barker 2016, 424).

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Limitations of Induced Pluripotent Stem Cells for Clinical Applications Much of the interest in pluripotent stem cells derives from their potential for clinical applications. Safety will be a significant factor in evaluating the appropriateness of clinical applications of pluripotent stem cell derivatives, particularly whether human induced pluripotent stem cell derivatives can meet the quality, stability, and purity standards required for human medical use. A 2011 review of the scientific literature titled “The dark side of induced pluripotency” concluded that the reprogramming process and subsequent culture of induced pluripotent stem cells in vitro induce genetic and epigenetic abnormalities in these cells that are likely to affect their safe use (Pera 2011). Shinya Yamanaka has taken issue with this assessment, but without denying the factors leading to this conclusion (Yamanaka 2012). In making the determination about the safety of induced pluripotent stem cell derivatives, it is important to keep in mind that these cells have undergone a tremendous amount of genetic manipulation that is likely to contribute to their genetic instability (Hyun 2013, 35). Both human embryonic stem cells and human induced stem cells have been shown to have genetic aberrations, but human induced pluripotent cell derivatives appear to have more fundamental problems and a much greater number and type of abnormalities than human embryonic stem cells (Laurent et al. 2011). These variations include aneuploidy (an abnormality in chromosome number), subchromosomal copy number variations (a phenomenon in which sections of the genome are duplicated), and single-nucleotide variations. Studies have shown that these singlenucleotide variations exist between induced pluripotent stem cell lines, between induced pluripotent and embryonic stem cell lines, and even between different populations from a specific passage of the same induced pluripotent stem cell line. These variations potentially affect the properties of induced pluripotent stem cells and their reliability in downstream applications (Liang and Zhang 2013).

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Some of the mutations observed in induced pluripotent stem cells are likely to be from the adult cells from which they are developed, others from the regression process, and still others from the time spent in culture. One study, which reprogrammed 22 human induced pluripotent stem cell lines using five different methods, resulted in an average of five proteincoding mutations. Half of the mutations preexisted in fibroblast progenitors at low frequencies, while the rest were newly occurring during or after reprogramming (Gore et al. 2011). Unlike embryonic stem cells, whose source is at the very beginning of life and therefore free from age-related mutations, induced pluripotent stem cells are derived from adult cells that have collected mutations over time. Furthermore, the frequency of mutations in induced pluripotent stem cells is estimated to be ten times higher than in the tissue from which they are derived (Pera 2011, 46). Studies have also shown that exomic mutations in induced pluripotent stem cells increase linearly with age. Many of the intended applications of induced pluripotent stem cells for autologous therapy would likely be using tissue derived from older patients (Lo Sardo et al. 2017). The possibility that the reprogramming process itself may be mutagenic and introduce de novo variations is particularly problematic. The generation of induced pluripotent stem cells involves resetting epigenetic parameters that affect the expression of genes. The incorrect setting of certain genes could cause overgrowth with a resulting cancer risk or undergrowth with an inability to compete with endogenous cells. Induced pluripotent stem cells frequently have both whole-chromosome epigenetic variability on the X chromosome and local epigenetic variations in other parts of the chromosome. During reprogramming, DNA methylation status may also be erroneously altered (Liang and Zhang 2013). Yet another limitation is that induced pluripotent stem cells have been shown to retain an epigenetic memory, a term that refers to persisting epigenetic markers characteristic of their tissue of origin. This epigenetic memory favors their differentiation along lineages related to the donor cell and restricts alternative cell fates (Vaskova et al. 2013; Narsinh, Plews, and Wu 2011; Kim et al. 2010). Some research has also shown that induced pluripotent stem cells appear to undergo premature senescence even in their early growth phase. This phenomenon has not been observed with embryonic stem cells. Whether these defects are cell line–specific or a broader problem with induced pluripotent stem cells requires further research to determine (Feng et al. 2010; Rohani et al. 2014). Additionally, human induced pluripotent stem cells appear to have a greater risk of tumor formation than human embryonic stem cells. Also

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worrisome, some of the genetic mutations in induced pluripotent stem cells appear in genes that have been linked to cancer. Studies have shown that the reprogramming process for induced pluripotent stem cells was associated with the deletion of tumor suppressor genes and that time in culture was associated with duplication of oncogenic genes (Laurent et al. 2011). Because the efficiency of the process of deriving induced pluripotent stem cells remains very low – typically less than one percent of transfected fibroblasts become induced pluripotent stem cells – this raises the possibility that induced pluripotent stem cells and undifferentiated cells coexist in fibroblast cultures (Yamanaka 2012). Implanting undifferentiated cells would further raise the risks of triggering oncogenic genes. Pluripotent stem cells used for clinical applications will have to be of higher quality and meet more stringent requirements than the pluripotent stem cells used for research. At the least, this indicates a need for developing comprehensive screens to assess the stem cell lines to be used. One suggestion is that karyotyping should be introduced as a standard postreprogramming protocol for induced pluripotent stem cells. It may also be advisable to conduct complete exome or genome sequencing of both embryonic stem cells and induced pluripotent stem cells to help establish clinical safety standards for genomic integrity (Gore et al. 2011, 201, 66). But it may also require that the mutational load identified here be reduced before induced pluripotent stem cells are employed in a clinical setting (Brouwer, Zhou, and Nadif Kasri 2016, 66).

Comparisons of the Two Types of Pluripotent Stem Cells in Publications and Clinical Trials A survey of articles published between 2008 and 2013 on human embryonic and induced pluripotent stem cell research based on searches of the PubMed database identified a pool of 2,922 studies reporting on experimental uses of human embryonic stem cells and 1,376 studies reporting on experimental use of human induced pluripotent stem cells. An analysis of the topics the papers addressed indicated that human embryonic stem cells and human induced stem cells were often used to answer somewhat different questions. The focus of the human embryonic stem cell research included basic research on cell pluripotency and plasticity, analysis of developmental mechanisms, and the provision of cell models for drug development and toxicity testing. In comparison, human induced pluripotent stem cell publications dominated the field of disease modeling, frequently in conjunction with the derivation of novel disease-specific human embryonic stem cell lines. The survey also reported that there were then 11 clinical

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trials registered with the FDA in which human embryonic stem cells were being used, primarily to develop treatments for different forms of macular degeneration, but also for neurological, cardiac, and pancreatic applications. There was only one clinical trial in the database using human induced pluripotent stem cells, the RIKEN trial for macular degeneration in Japan (Kobold et al. 2015). This research group also conducted an analysis of trends in stem cell research papers reporting on original experimental research published between 2014 and 2016. Their findings indicated that there was a considerable increase in human induced pluripotent stem cell research during those years, while human embryonic stem cell research also continued to grow, albeit at a slower pace. Publications on human induced pluripotent stem cells outstripped human embryonic stem cells as of 2015. Notably, an increasing percentage of the novel human embryonic stem cell lines identified in the publications were either derived from preimplantation genetic diagnosis embryos to model genetically inherited diseases or were clinical grade lines produced for future clinical applications. As with the previous survey, the analysis showed that a few human embryonic stem cell lines, three of the five oldest lines derived and characterized by James Thomson, continued to be the most commonly used (Guhr et al. 2018). As of the time of the survey, many more human embryonic stem cell based therapies than induced pluripotent stem cell–based products had advanced to human clinical trials. The numbers cited were 29 versus three. Most of these were early stage trials to test safety in small patient cohorts. With regard to the human induced pluripotent stem cell trials, only one of the three trials that had then been approved was planned to be performed with autologous cell products derived from the patient’s own cells (Guhr et al. 2018). As noted earlier in the chapter, that trial was stopped because of mutations with unknown potential risk in the human induced pluripotent stem cell source material, with researchers planning to restart the trial with allogenic lines. Chapter Six will offer a more in-depth analysis of these early clinical trials. The trends in the field are not surprising. As indicated above, working with human induced pluripotent stem cells is simpler in many regards than the requirements for research with human embryonic stem cells. Stem cell researchers at my own institution, UConn Health, confirmed that many researchers choose to conduct research with induced pluripotent stem cells to avoid the regulatory requirements for human embryonic stem cells and the need to obtain a material transfer agreement for the human embryonic stem cell lines. Some funders may also be more inclined to support research with induced pluripotent stem cell lines. When it comes to

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clinical trials, though, there is a different calculus. Concerns about the safety of human induced pluripotent stem cells likely explain the continuing preference for human embryonic stem cell applications for clinical trials. Nevertheless, other clinical trials with induced pluripotent stem cells are in process. In October 2018, as part of a clinical trial, Japanese scientists implanted the first Parkinson’s patient with replacement neurons derived from skin cells from a healthy donor and reprogrammed into induced pluripotent stem cells (Penumetcha 2018). A study undergoing FDA review for approval to begin the trial will also test the therapeutic potential of transplanting dopamine neurons from induced pluripotent stem cells into patients with Parkinson’s disease. The trial will generate induced pluripotent stem cells from patients’ skin cells, on the assumption that this will reduce the possibility of rejection (Rubin 2018). Japan continues to provide strong support and funding for induced pluripotent stem cell research, particularly after the awarding of the 2012 Nobel medicine prize to Japanese scientist Shinya Yamanaka for his discovery of induced pluripotent stem cells. According to one article, “What started in 2007 as Japan’s cautious excitement over the human [induced pluripotent stem] cells as both a ‘made in Japan’ source of new therapies and a powerful accelerant for drug development has been transformed into an article of national faith” (Lewis and Cookson 2017). Japan’s investment in induced pluripotent stem cells has also been described as Japan’s scientific moonshot. To create a new industry around induced pluripotent stem cells, the government is promoting commercialization of induced pluripotent cell technology, and corporate Japan is investing in the technology in Europe, North America, and elsewhere in Asia (Lewis and Cookson 2017). In addition, as will be discussed in the next chapter, the Japanese government has adopted a new law intended to accelerate the approval of regenerative therapies and the commercialization of stem cell therapies within the country by providing an accelerated conditional approval pathway that eliminates the need for Phase III clinical trials. As of early 2018, three new regenerative medicine products were conditionally approved and an early-stage induced pluripotent stem cell trial for a heart therapy was initiated (Sietsema et al. 2018).

Reflections As the introduction to this chapter indicates, the choice of the stem cell type for research and the development of therapies has significant ethical as well as scientific implications. Up to now the discussion of the ethical implications of pluripotent stem cell research has focused on the question

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of the ethical permissibility of using human embryonic stem cells. Chapter One outlined the diversity of perspectives in the religious as well as the secular community about deriving human embryonic stem cells from the inner cell mass of blastocysts. However, the introduction to this chapter pointed out that the therapeutic potential of the type of stem cell selected is also an important ethical consideration. After all, the development of therapies to relieve human suffering is a moral priority and the primary impetus underlying the development of the stem cell field. Therefore, this chapter also assessed ethical issues in the context of scientific developments. It will most likely not come as a surprise that, for the reasons cited in this chapter, I concur with those ethicists, religious thinkers, and scientists who consider the derivation of and research with human embryonic stem cells to be ethically permissible. I do not think that an early preimplantation embryo of 150 to 200 cells, technically a blastocyst, located outside of a mother’s body should be treated as having the same moral status as an implanted embryo approaching viability – and even less that it deserves protections on par with a person after birth. The potential to become something is not the same as actually already being that something. Nor does that potential being have the same moral significance as the actual being that it might become. Moreover, scientific research has shown that the majority of early implanted embryos, around two thirds of all conceptions, die early in pregnancy, mostly because of genetic abnormalities, and therefore do not have the opportunity to become actual persons (Norwitz, Schust, and Fisher 2001). Also, if not used for scientific research, the surplus embryos left over from fertility treatment and the embryos of poor quality that are unsuitable for implantation, which are the two types of embryos that are typically used to derive human embryonic stem cell lines, would otherwise be destroyed or kept frozen indefinitely, as some one million early embryos have been. However, I do believe that the early embryo does deserve some respect beyond that generally given to other cells from the human body. I would therefore add the proviso that, to be ethical, the derivation of embryonic stem cell lines should be performed under rigorous scientific and ethical oversight. Moreover, any new derivation of embryonic stem cell lines should be for significant scientific research projects likely to be of public benefit. The same criteria apply to research with the thousands of already existing embryonic stem cell lines. They should not be used for frivolous purposes. When it comes to the choice of the type of stem cells most likely to be appropriate for developing clinical therapies, I believe that human embryonic stem cells have the scientific and therefore the ethical edge as

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well. This chapter has identified the many limitations of induced pluripotent stem cells for clinical applications, most of which are not shared by human embryonic stem cells. As one stem cell researcher, whose own research focuses on human induced pluripotent stem cells, stated in response to my inquiry about the suitability of induced pluripotent stem cells for clinical applications: “For clinical trials and applications, though, [induced pluripotent stem cells] introduce some worrisome variables.” As the literature cited in this chapter indicates, there is reason to be concerned. At least up to the time of writing, far more therapies are in clinical trials using human embryonic stem cells than human induced pluripotent stem cells. However, the determination of the Japanese government to develop an induced pluripotent stem cell juggernaut and the reluctance of some other funders to support research and clinical trials with human embryonic stem cells may change the equation in the future. This is troubling. For these reasons, I believe that going forward with human embryonic stem cell research for the development of therapies to relieve human suffering is a moral priority that is in the public interest. Otherwise, “By sidelining the cells with the greatest growth capacity and plasticity on the basis of moral objections, the regenerative potential of stem cells is left unfulfilled” (Poulos 2018, 21). Moreover, as noted in this chapter, I believe these moral objections are misapplied.

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References Andrzejewska, Anna, Barbara Lukomska, and Miroslaw Janowski (2019) “Concise Review: Mesenchymal Stem Cells: From Roots to Boost.” Stem Cells 37 (7): 855–64. Blair, Nicholas F., and Roger A. Barker (2016) “Making It Personal: The Prospects for Autologous Pluripotent Stem Cell-Derived Therapies.” Regenerative Medicine 11 (5): 423–25. Borlongam, Cesario V. (2019) “Concise Review: Stem Cell Therapy for Stroke Patients: Are We There yet?” Stem Cells Translational Medicine 8 (9): 983–88. Brouwer, Marinka, Huiqing Zhou, and Nael Nadif Kasri (2016) “Choices for Induction of Pluripotency: Recent Developments in Human Induced Pluripotent Stem Cell Reprogramming Strategies.” Stem Cell Reviews and Reports 12: 54–72. Brown, Mark T. (2009) “Moral Complicity in Induced Pluripotent Stem Cell Research.” Kennedy Institute of Ethics Journal 19 (1): 1–22.

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Chapman, Audrey R. (2015) “Induced Pluripotent Cells: Ethical Answer or a Source of Continuing Ethical Dilemmas?” In Advanced Therapies in Regenerative Medicine, edited by Jan-Thorsten Schantz and Dietmar W. Hutmacher, 1–20. New Jersey: World Scientific Publishing Company. Chapman, Audrey R. (2019) “What Can We Learn from California Institute for Regenerative Medicine’s First 50 Clinical Trials?” Regenerative Medicine 14 (10): 899–903. Chin, Mark H., Mike J. Mason, Wei Xie, Stefano Volinia, Mike Singer, Cory Peterson, Gayane Ambartsumyan, et al. (2009) “Induced Pluripotent Stem Cells and Embryonic Stem Cells Are Distinguished by Gene Expression Signatures.” Cell Stem Cell 5 (1): 111–23. Curzer, Howard J. (2004) “The Ethics of Embryonic Stem Cell Research.” The Journal of Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine 29 (5): 533–62. 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. Daley, George Q. (2012) “The Promise and Perils of Stem Cell Therapeutics.” Cell Stem Cell 10 (6): 740–49. Daughtry, Brittany, and Shoukhrat Mitalipov (2014) “Concise Review: Parthenote Stem Cells for Regenerative Medicine: Genetic, Epigenetic, and Developmental Features.” Stem Cells Translational Medicine 3 (3): 290–98. Deuse, Tobias, Xiaomeng Hu, Alessia Gravina, Dong Wang, Grigol Tediashvili, Chandrav De, William O. Thayer, et al. (2019) “Hypoimmunogenic Derivatives of Induced Pluripotent Stem Cells Evade Immune Rejection in Fully Immunocompetent Allogeneic Recipients.” Nature Biotechnology 37 (3): 252–58. Devolder, Katrien (2009) “To Be, or Not to Be?” EMBO Reports 10 (12): 1285–7. Devolder, Katrien (2010) “Complicity in Stem Cell Research: The Case of Induced Pluripotent Stem Cells.” Human Reproduction 25 (9): 2175– 80. Doerflinger, Richard M. (1999) “The Ethics of Funding Embryonic Stem Cell Research: A Catholic Viewpoint.” Kennedy Institute of Ethics Journal 9 (2): 137–50. Doi, Akiko, In-Hyun Park, Bo Wen, Peter Murakami, Martin J. Aryee, Rafael Irizarry, Brian Herb, et al. (2009) “Differential Methylation of Tissue- and Cancer-Specific CpG Island Shores Distinguishes Human Induced Pluripotent Stem Cells, Embryonic Stem Cells and Fibroblasts.” Nature Genetics 41 (12): 1350–3.

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Ellit, Matthew S., Lilianne Barbar, and Paul J. Tesar (2018) “Drug Screening for Human Genetic Diseases Using iPSC Models.” Human Molecular Genetics 27 (R2): R89–R98. Expert Advisory Panel on Prochymal (2012) “Report of the Expert Advisory Panel on Prochymal.” Health Canada. https://www.canada.ca/en/health-canada/services/drugs-healthproducts/biologics-radiopharmaceuticals-genetic-therapies/activities/ scientific-expert-advisory-panels/prochymal/report-prochymal.html. Feng, Qiang, Shi-Jiang Lu, Irina Klimanskaya, Ignatius Gomes, Dohoon Kim, Young Chung, George R. Honig, Kwang-Soo Kim, and Robert Lanza (2010) “Hemangioblastic Derivatives from Human Induced Pluripotent Stem Cells Exhibit Limited Expansion and Early Senescence.” Stem Cells 28 (4): 704–12. Filho, Daniel Mendes, Patrícia de Carvalho Ribeiro, Lucas Felipe Oliveira, Ana Luiza Romero Terra dos Santos, Ricardo Cambraia Parreira, Mauro Cunha Xavier Pinto, and Rodrigo Ribeiro Resende (2019) “Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with the CRISPRCas System.” Stem Cell Reviews and Reports 15 (4): 463–73. Garber, Ken (2015) “RIKEN Suspends First Clinical Trial Involving Induced Pluripotent Stem Cells.” Nature Biotechnology 33 (9): 890–91. Gore, Athurva, Zhe Li, Ho-Lim Fung, Jessica E. Young, Suneet Agarwal, Jessica Antosiewicz-Bourget, Isabel Canto, et al. (2011) “Somatic Coding Mutations in Human Induced Pluripotent Stem Cells.” Nature 471 (7336): 63–67. Guhr, Anke, Sabine Kobold, Stefanie Seltmann, Andrea E. M. Seiler Wulczyn, Andreas Kurtz, and Peter Löser (2018) “Recent Trends in Research with Human Pluripotent Stem Cells: Impact of Research and Use of Cell Lines in Experimental Research and Clinical Trials.” Stem Cell Reports 11 (2): 485–96. Holden, Constance, and Gretchen Vogel (2008) “A Seismic Shift for Stem Cell Research.” Science 319 (5863): 560–63. Hu, Bao-Yang, Jason P. Weick, Junying Yu, Li-Xiang Ma, Xiao-Qing Zhang, James A. Thomson, and Su-Chun Zhang (2010) “Neural Differentiation of Human Induced Pluripotent Stem Cells Follows Developmental Principles but with Variable Potency.” Proceedings of the National Academy of Sciences 107 (9): 4335–40. Hyun, Insoo (2008) “Stem Cells from Skin Cells: The Ethical Questions.” The Hastings Center Report 38 (1): 20–22. Hyun, Insoo (2013) “The Embryo Potentiality Argument Revisited: ‘Once More Unto the Breach, Dear Friends’.” The American Journal of Bioethics 13 (1): 28–29.

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Hyun, Insoo, Konrad Hochedlinger, Rudolf Jaenisch, and Shinya Yamanaka (2007) “New Advances in iPS Cell Research Do Not Obviate the Need for Human Embryonic Stem Cells.” Cell Stem Cell 1 (4): 367– 68. Institute of Medicine and National Research Council (2005) Guidelines for Human Embryonic Stem Cell Research. Washington, DC: The National Academies Press. Kim, K., A. Doi, B. Wen, K. Ng, R. Zhao, P. Cahan, J. Kim, et al. (2010) “Epigenetic Memory in Induced Pluripotent Stem Cells.” Nature 467 (7313): 285–90. Klimanskaya, Irina, Young Chung, Sandy Becker, Shi-Jiang Lu, and Robert Lanza (2006) “Human Embryonic Stem Cell Lines Derived from Single Blastomeres.” Nature 444 (7118): 481–85. Kobold, Sabine, Anke Guhr, Andreas Kurtz, and Peter Löser (2015) “Human Embryonic and Induced Pluripotent Stem Cell Research Trends: Complementation and Diversification of the Field.” Stem Cell Reports 4 (5): 914–25. Laurent, Louise C., Igor Ulitsky, Ileana Slavin, Ha Tran, Andrew Schork, Robert Morey, Candace Lynch, et al. (2011) “Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs During Reprogramming and Time in Culture.” Cell Stem Cell 8 (1): 106–18. Lewis, Leo, and Clive Cookson (2017) “Stem Cells: Japan’s Scientific ‘Moonshot’.” Financial Times. https://www.ft.com/content/254853b28f23-11e7-9084-d0c17942ba93. Liang, Gaoyang, and Yi Zhang (2013) “Genetic and Epigenetic Variations in iPSCs: Potential Causes and Implications for Application.” Cell Stem Cell 13 (2): 149–59. Lo Sardo, Valentina, William Ferguson, Galina A. Erikson, Eric J. Topol, Kristin K. Baldwin, and Ali Torkamani (2017) “Influence of Donor Age on Induced Pluripotent Stem Cells.” Nature Biotechnology 35: 69–74. Narsinh, Kazim H., Jordan Plews, and Joseph C. Wu (2011) “Comparison of Human Induced Pluripotent and Embryonic Stem Cells: Fraternal or Identical Twins?” Molecular Therapy 19 (4): 635–38. 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. Norwitz, Errol R., Danny J. Schust, and Susan J. Fisher (2001) “Implantation and the Survival of Early Pregnancy.” New England Journal of Medicine 345 (19): 1400–1408.

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Parrotta, Elvira, Maria Teresa De Angelis, Stefania Scalise, Patrizio Candeloro, Gianluca Santamaria, Mariagrazia Paonessa, Maria Laura Coluccio, et al. (2017) “Two Sides of the Same Coin? Unraveling Subtle Differences Between Human Embryonic and Induced Pluripotent Stem Cells by Raman Spectroscopy.” Stem Cell Research & Therapy 8: 271. Penumetcha, Pallavi (2018) “Japanese Scientists Implant First Parkinson’s Patient with Replacement Neurons Derived from Stem Cells.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, November. https://blog.cirm.ca.gov/2018/11/26/japanese-scientistsimplant-first-parkinsons-patient-with-replacement-neurons-derivedfrom-stem-cells/. Pera, Martin F. (2011) “The Dark Side of Induced Pluripotency.” Nature 471 (7336): 46–47. Peters, Ted (2007) The Stem Cell Debate. Minneapolis, MN: Fortress Press. Poulos, Jordan (2018) “The Limited Application of Stem Cells in Medicine: A Review.” Stem Cell Research & Therapy 9: 1. Robinton, Daisy A., and George Q. Daley (2012) “The Promise of Induced Pluripotent Stem Cells in Research and Therapy.” Nature 481 (7381): 295–305. Rohani, Leili, Adiv A. Johnson, Antje Arnold, and Alexandra Stolzing (2014) “The Aging Signature: A Hallmark of Induced Pluripotent Stem Cells?” Aging Cell 13 (1): 2–7. Rowe, R. Grant, and George Q. Daley (2019) “Induced Pluripotent Stem Cells in Disease Modelling and Drug Discovery.” Nature Reviews Genetics 20 (7): 377–88. Rubin, Rita (2018) “Unproven but Profitable: The Boom in US Stem Cell Clinics.” JAMA 320 (14): 1421–3. Sietsema, William K., Yoshiyuki Takahashi, Kosuke Ando, Tetsuro Seki, Atsuhiko Kawamoto, and Douglas W. Losordo (2018) “Japan’s Conditional Approval Pathway for Regenerative Medicines.” Regulatory Focus, May. Vaskova, E. A., A. E. Stekleneva, S. P. Medvedev, and S. M. Zakian (2013) “‘Epigenetic Memory’ Phenomenon in Induced Pluripotent Stem Cells.” Acta Naturae 5 (4): 15–21. Yamanaka, Shinya (2012) “Induced Pluripotent Stem Cells: Past, Present, and Future.” Cell Stem Cell 10 (6): 678–84. Zhao, Tongbiao, Zhen-Ning Zhang, Zhili Rong, and Yang Xu (2011) “Immunogenicity of Induced Pluripotent Stem Cells.” Nature 474 (7350): 212–15.

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CHAPTER THREE

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REGULATIONS, GUIDELINES, AND OVERSIGHT MECHANISMS

The responsible conduct of scientific research and its ethical translation into therapies, especially in an innovative and complex field, require guidelines and regulations, preferably ones informed by explicit ethical norms, as well as oversight mechanisms. Guidelines and regulations can play an important role in reassuring the public that the research is being conducted ethically and responsibly. The ethical practice of research and the translation of research into therapies is especially relevant in the case of a controversial field of research with a host of significant ethical questions and that may have a public impact. As Cynthia Cohen has noted, “When an innovative area of scientific research emerges that promises to revolutionize the lives and health of many within society and yet is permeated with significant ethical challenges, it does not remain a private activity, but becomes a public endeavor” (Cohen 2007, 198–99). Recognizing the importance of providing such guidance for the gene therapy (gene transfer) field, the National Institutes of Health (NIH) set guidelines and established the Recombinant DNA Advisory Committee (RAC) soon after the inception of this emerging biotechnology. What made this research deserving of additional oversight? In 1974, when the RAC was instituted, gene therapy research involved the introduction of somatic cell genetic modifications in individuals with serious medical problems through techniques that were novel, carried high risk, and had uncertain consequences. Additionally, the clinical trials subject to RAC review often represented first uses in humans (Kahn and Mastroianni 2018). The same factors characterize pluripotent stem cell research and clinical translation. Pluripotent stem cell research similarly is high-stakes, innovative research that has attracted considerable public interest and concern. As in gene therapy, most of the clinical trials in this field are firstin-human applications and involve individuals with serious medical problems. However, the field has been treated differently by the U.S. federal government, which has not established a national oversight body. Neither

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has the NIH or the Food and Drug Administration (FDA) developed guidelines specifically for pluripotent stem cell research or for the conduct of clinical trials with therapies developed from pluripotent stem cells, even after FDA advisory bodies have noted that pluripotent stem cells raise unique issues (Food and Drug Administration 2008, 8). This has meant that federal regulations drafted for other purposes have been applied to pluripotent stem cell research and trials. As in other countries, a central government agency (the FDA) does regulate biologics and stem cell therapies entering clinical trials, and stem cell therapies are similarly subject to premarket approval. This chapter will review and evaluate how pluripotent stem cell research is being regulated and monitored in the U.S., with some references to the United Kingdom and Japan. It will review the guidelines for stem cell research and clinical translation published by the National Academy of Sciences, a prestigious private institution that provides expert advice on scientific issues to the federal government, and by the International Society for Stem Cell Research (ISSCR), the most significant international professional organization engaged with stem cell research. Issues, guidelines, and regulation specific to clinical trials will be dealt with in Chapter Six. The lack of a dedicated regulatory body for pluripotent stem cell research in the U.S. has resulted in institutionally based stem cell review committees playing a key role in reviewing the ethical and scientific appropriateness of individual protocols. These operate much like institutional review boards (IRBs), but they do not have national guidelines to inform their work. 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.

Stem Cell Research Guidelines and Regulations in the United States As noted in Chapter One, in 1998, when scientists announced they had isolated and cultured human embryonic stem cells, President William (Bill) Clinton asked the National Bioethics Advisory Commission (NBAC), an advisory body he had established in 1995, to conduct a review of the issues associated with human stem cell research. NBAC recommended proceeding with human embryonic research and proposed making federal funds available for both the derivation of embryonic stem cell lines from embryos remaining after fertility treatment and research with human embryonic stem cells. However, before NBAC could issue its report, the Clinton administration

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announced that no federal funding would be forthcoming to derive human embryonic stem cell lines. The Clinton administration likely viewed funding anything that directly involved the destruction of embryos as politically perilous and worried that it might be interpreted as contravening the Dickey–Wicker Amendment, which was attached annually to the funding bill for the Department of Health and Human Services. The Dickey–Wicker Amendment prohibits the federal government from funding any research resulting in harm to or the destruction of an embryo. President Clinton then turned to the National Institutes of Health (NIH) to develop guidelines for human embryonic stem cell research. The NIH issued its guidelines in August 2000 and began accepting grant applications for research projects using human embryonic stem cells. However, before NIH’s Human Pluripotent Stem Cell Review Group held its first meeting, George W. Bush became the President of the United States, adopting a different policy calculus. The Clinton NIH guidelines for stem cell research were formally withdrawn in November 2001 (Cohen 2007, 166–71). Contrary to widespread expectations that President Bush, who had represented himself as a right-to-life advocate during the campaign, would not fund human embryonic stem cell research, he announced in a nationally televised speech made in August 2001 that he had decided to support federal funding for embryonic stem cell research. He did add the proviso that he would restrict eligibility to the human embryonic stem cell lines already in existence as of the date of his speech. The rationale for this policy was that the federal government could fund a promising new area of medical research, without being a party to the destruction of human embryos or encouraging researchers to do so. NIH set four criteria for funding based on President Bush’s speech: (1) the stem cells were derived from an embryo created for reproductive purposes; (2) the embryo was no longer needed for these purposes; (3) informed consent had been obtained for the donation of the embryo; and (4) no financial inducements were provided for the donation of the embryo. NIH then established a registry of the human embryonic stem cell lines that met these eligibility criteria (National Institutes of Health 2001). The Bush administration’s minimalist approach evoked criticism from opponents of stem cell research, and did not satisfy supporters, either. The NIH registry had identified only twenty-two stem cell lines that met President Bush’s eligibility criteria, not the 60 plus lines that had been assumed to be in existence at the time of his speech, and some of these lines were not available or suitable for research. Subsequently, Congress made two attempts to pass legislation to expand the number of embryonic stem cell lines eligible for federal funding, but both bills were vetoed by the President. The Bush policy meant that institutions conducting

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human embryonic stem cell research which wished to use lines not on the federal registry had to maintain separate laboratories with equipment not obtained from federal grants. The limited funding and restricted eligibility of stem cell lines encouraged states, foundations, and small private companies to provide additional unrestricted sources of research funding for the field. Likely because of the ethical controversy and opposition to human embryonic stem cell research, particularly among his supporters, the Bush administration did not ask NIH to provide guidelines for human embryonic stem cell research. Nor did it establish a national body to provide oversight for human embryonic stem cell research that could offer the kind of constructive guidance the RAC had provided for gene transfer research and trials. This left a new and controversial field of research without federal guidance and oversight in the country that was to have the largest research enterprise in the field.

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The National Academy of Sciences Guidelines for Human Embryonic Stem Cell Research The National Academies of Science (NAS) stepped into this policy and ethical vacuum. Using funds provided by several private foundations, it established a Human Embryonic Stem Cell Embryonic Stem Cell Research Advisory Committee composed of eminent scientists, lawyers, and ethicists in the stem cell field with the mandate to draft a set of guidelines for the conduct of human embryonic stem cell research. Their guidelines were first published in 2005 (Institute of Medicine and National Research Council 2005) and then updated annually through 2010 when NAS ran out of grant money for this purpose. The 2008 amendments extend the guidelines to cover human induced pluripotent stem cell research (Institute of Medicine and National Research Council 2008). The NAS Guidelines have provided a basic framework for embryonic stem cell research that many institutional stem cell oversight bodies have adopted. Some of the states that fund stem cell research have also taken sections of the guidelines as the basis for their legal framework. However, these guidelines, as useful as they are, do not address many of the ethical issues raised by human embryonic stem cell research. Importantly, except in those states enacting portions of the Guidelines into law, the Guidelines were voluntary and “do not provide a full-scale national policy directive for pluripotent stem cell research, although they represent a significant and useful first set” (Cohen and Majumder 2009, 83). However, as noted, the federal government has not supplemented or replaced the NAS

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Guidelines with a more comprehensive set of national regulations. Although there are some aspects of pluripotent stem cell research that fall under federal regulations drafted for other purposes, pluripotent stem cell research has generally proceeded according to an institutional and state patchwork of regulations and policies (Cohen and Majumder 2009, 83). The NAS Committee on Guidelines for Human Embryonic Stem Cell Research linked the need for the guidelines to the void left by the restriction of federal funding and its attendant oversight of research and to the importance that the scientific and biomedical community attach to pursuing this new field of research. According to the Committee, the substantial public support for human embryonic stem cell research and the growing trend by many state legislatures and other funding agencies to support the field warranted heightened oversight to assure the public that such research can and will be conducted ethically (Institute of Medicine and National Research Council 2005, 19). It also cited the need to offer assurance to the public and to Congress that the scientific community would respect the special moral status of the human embryo and be sensitive to the fact that some people believe the research to be morally unacceptable (Institute of Medicine and National Research Council 2005, 52). The 2005 NAS Guidelines consist of 23 recommendations of varying levels of specificity. A central recommendation in the Guidelines is that all institutions conducting human embryonic stem cell research should establish an Embryonic Stem Cell Research Oversight (ESCRO) committee to provide oversight of all issues related to the derivation and use of human embryonic stem cell lines. The Guidelines explain that the complexity and novelty of many of the issues involved in human embryonic stem cell research warrant research institutions doing so. In order for the oversight committee to have broad expertise, the Guidelines specify that its membership should include representatives of the public and persons with backgrounds in developmental biology, stem cell research, molecular biology, assisted reproduction, and ethical and legal issues related to human embryonic stem cell research. The Guidelines explain that this committee is not intended to serve as a substitute for an institutional review board but instead would provide an additional level of review and scrutiny (Institute of Medicine and National Research Council 2005, 53, 56). This may be the most influential of the NAS provisions. The guidelines also offer detailed guidance on the donation of gametes and embryos for embryonic stem cell research. The roles the NAS Guidelines assign to ESCRO committees are quite broad. These committees are instructed to:

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1. Provide oversight for all issues related to derivation and use of hES cell lines. 2. Review and approve the scientific merit of research protocols. 3. Review compliance of all-in house hES cell research with all relevant regulations and [these guidelines]. 4. Maintain registries of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators. 5. Facilitate education of investigators involved in hES research (Institute of Medicine and National Research Council 2005, 53). The NAS Guidelines identify three types of research that should not be permitted at this time. They are (1) research involving in vitro culture of any intact human embryo for longer than fourteen days or until formation of the primitive streak begins, whichever occurs first; (2) research in which human embryonic stem cells are introduced into nonhuman primate blastocysts; and (3) research in which embryonic stem cells are introduced into human blastocysts (Institute of Medicine and National Research Council 2005, 57). The Guidelines also caution that no animal into which human embryonic stem cells have been introduced should be allowed to breed (Institute of Medicine and National Research Council 2005, 58). The fourteen-day limit for maintaining an embryo in culture has been widely adopted across scientific fields. Given the similarity between human and nonhuman primate genomes, the introduction of human embryonic stem cells into a nonhuman primate blastocyst would run the risk of humanizing the nonhuman primate in some significant ways. Similarly, there was concern that breeding two animals implanted with human embryonic stem cells might result in their offspring having some human characteristics, something many would find deeply problematic. The Guidelines underscore the importance of adhering to strict standards of informed consent for prospective donors of gametes and blastocysts for stem cell research. The Guidelines direct that, to the extent possible, consent for donation should be obtained from each donor at the time of donation, even in the case of people who have given prior indication of their intent to donate to research. In addition, the Guidelines state that potential donors should be informed of the array of possible future research uses at a level that is readily understandable and will facilitate an informed decision. The Guidelines also mandate that consenting or refusing to donate gametes or blastocysts for research should not affect the quality of clinical care provided to prospective donors. (Institute of Medicine and National Research Council 2005, 10–11).

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Because generating new human embryonic stem cell lines, even obtaining gametes or blastocysts for that purpose, is sensitive and ethically fraught, the Guidelines incorporate several safeguards. The first is that an institutional review board or its equivalent should review the procurement of gametes, blastocysts, or somatic cells acquired for generating new human embryonic stem cell lines (Institute of Medicine and National Research Council 2005, 9). The Guidelines also assign the Embryonic Stem Cell Committee the task of evaluating all requests to attempt derivation of new human embryonic stem cell lines, specifying that the scientific rationale for generating new lines must be clearly indicated along with the basis for the number of blastocysts needed. These requests are to be accompanied by evidence of institutional review board approval of the procurement process (Institute of Medicine and National Research Council 2005, 57). To facilitate and protect the autonomous choice of prospective donors, the Guidelines specify that, whenever it is practicable, the attending physician responsible for the fertility treatment and the investigator deriving or proposing to use human embryonic stem cells should not be the same person (Institute of Medicine and National Research Council 2005, 101). Additionally, to discourage the production of embryos in excess of what is needed for fertility treatment, so as to have them available for human embryonic stem cell research, the Guidelines direct that no cash or in-kind payments may be provided for donating blastocysts (Institute of Medicine and National Research Council 2005, 101). The NAS Guidelines call for the establishment of a national body to assess periodically the adequacy of the guidelines it has proposed. The Guidelines envision this national body as a forum for a continuing discussion of issues involved in human embryonic stem cell research but not serving as a centralized body to review individual protocols on the model of the Recombinant DNA Review Committee, possibly because the Committee realized that this was unlikely to occur. The document points out that national review bodies have been established in most countries in which human embryonic stem cell research is permitted, usually under government auspices (Institute of Medicine and National Research Council 2005, 58–59). President Clinton’s National Bioethics Advisory Commission’s report on Ethical Issues in Human Stem Cell Research had also identified the need for a National Stem Cell Oversight Review Panel to ensure that all federally funded human embryonic stem cell research would be conducted in conformity with ethical principles and the recommendations in its report (National Bioethics Advisory Commission 1999, 76). Unfortunately, such a body has never been established.

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The Guidelines also mention the need to provide for the just distribution of the potential benefits of human embryonic stem cell research. This concern has considerable relevance in a country with widespread inequalities in access to healthcare and where new medical therapies are often priced beyond the resources of most people and the acceptable levels of many health care insurers. To be able to implement this recommendation, the Guidelines propose that there be a concerted effort to ensure diversity in the genetic makeup of cell lines used for human embryonic stem cell research and in the approaches to clinical care, but it does not provide directions on how to accomplish these goals (Institute of Medicine and National Research Council 2005, 60), nor is it clear that greater diversity in the genetic makeup of cells would be necessary or sufficient to ensure the just distribution of potential benefits. As important as they are in providing an initial set of ethical standards for human embryonic stem cell research, the NAS Guidelines are limited in a number of ways. Because they are voluntary in nature, institutions can adopt the Guidelines in full or in part or reject them completely. The Guidelines are primarily procedural. They do not address substantive issues about how and why research should or should not be conducted. Possibly because clinical trials seemed many years away, the Guidelines do not deal with issues related to the conduct of clinical trials.

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2008 Amendments to the National Academies’ Guidelines Between 2006 and 2010, the Human Embryonic Stem Cell Research Advisory Committee issued annual amendments for its Guidelines. The 2008 amendments were the most significant among them because they addressed the applicability of the 2005 Guidelines to human induced pluripotent stem cell research. Many sections of the 2008 Amendments cite specific guidelines in the 2005 report and confirm their relevance to human induced pluripotent stem cells. To highlight a few areas: the 2008 Amendments again emphasize the importance of the informed consent process for donation of human tissue providing detailed information on what informed consent should include (Institute of Medicine and National Research Council 2008, 8). The Amendments also direct that an institutional review board (IRB) should review all new procurements of gametes, blastocysts, or somatic cells obtained for the purpose of generating new human embryonic or induced pluripotent stem cell lines (Human Embryonic Stem Cell Research Advisory Committee 2008,7). Addressing the issue of researchers who want to derive induced pluripotent stem cell lines from banked tissues obtained prior to the adoption of these revised guidelines, the

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Amendments state that it is permissible to do so provided the original donations were made in accordance with the legal requirements in force at the place and time of donation. The Amendments caution that if the banked tissues retain identifiers linked to living individuals, human subject protections may apply (Institute of Medicine and National Research Council 2008, 9). Importantly, the Amendments assign to human embryonic stem cell review committees many of the same functions of review and oversight of research with human induced pluripotent stem cells as the Guidelines had with respect to human embryonic stem cell research. This includes review of the provenance of these cells to ensure the cell lines were derived according to ethical procedures of informed consent (Institute of Medicine and National Research Council 2008, 11). One exception is that the Amendments state that the use of human induced pluripotent stem cells in purely in vitro experiments need not be subjected to review unless the experiments are designed or expected to develop gametes. However, while many of the Committee’s 2005 guidelines dealing with human embryonic stem cell research have been widely adopted, its guidelines for oversight of human induced pluripotent stem cell research have not. This difference apparently reflects the reluctance of many stem cell scientists to accept comprehensive review of this type of research. While they acknowledge that research with cell lines originally derived from embryos warrant oversight, they consider human induced pluripotent stem cells to be comparable to the human cells they had been transplanting into animals for decades – which of course they are not.

Embryonic Stem Cell/Stem Cell Research Oversight Committees As noted above, the NAS Guidelines propose that all institutions conducting human embryonic stem cell research establish a new type of institutional oversight committee, which they termed an embryonic stem cell research oversight committee (ESCRO). The Guidelines assign the ESCRO committee a wide range of functions. As Hank Greely points out, “The NAS Guidelines asked for a lot. They asked research institutions voluntarily to accept constraints on what research they could do and to spend the time, effort, and money to set up a wholly new self-regulatory system – and then to maintain that system indefinitely” (Greely 2013, 47). According to Greely, the single most remarkable thing about this recommendation is that many institutions did set up embryonic stem cell research oversight committees, and in some cases state laws and funders’ guidelines required them to do so (Greely 2013, 47).

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There have been two surveys to try to assess the number of institutions that did so. A 2007 survey conducted by the University of Connecticut two years after the publication of the 2005 NAS Guidelines found that 25 of these committees had been established, and a second informal survey by the Interstate Alliance for Stem Cell Research in 2011 identified 30 of these committees (Greely 2013, 47). Others have considered these numbers to be low given the many universities, research institutions, and companies that conduct and publish embryonic stem cell research (Devereaux and Kalichman 2013, 59). In terms of their roles, the Interstate Alliance’s 2011 informal survey indicated that the overwhelming majority of these committees had oversight responsibilities for the key functions for human embryonic stem cell research detailed in the NAS Guidelines. Moreover, more than half of the committees either had or were considering responsibilities beyond those described in the NAS Guidelines and/or state requirements (Interstate Alliance on Stem Cell Research 2011). In the absence of federal guidance, each of these committees has had to develop its own supplementary rules and procedures. There has been little research evaluating the operation of ESCRO committees or their impact on stem cell research. In one of the few articles written about such committees, Hank Greely, a Professor at Stanford Law School with experience as a member of such a committee, opined that the committees probably played some useful roles in preventing abuses as well as in applying the NAS guidelines in reasonable ways. However, he also claimed that their most important role may have been to enable states and foundations to fund human embryonic stem cell research and universities and other research institutions to conduct the research (Greely 2013, 51). Others have provided affirmations of the contributions of ESCRO committees and their benefit to the embryonic stem cell research field (Ellison 2013; Devereaux and Kalichman 2013; Brewer and DeGrote 2013; Lomax 2013; Chapman 2013).

National Institutes of Health’s 2009 Guidelines and Registry In March 2009, shortly after he took office, President Barack Obama signed an executive order revoking the restrictions on federal funding of embryonic stem cell research imposed in 2001 by President George W. Bush. In his remarks President Obama stated that the decision reflected not only his views but also a broad social consensus. He also asked the Director of the National Institutes of Health to determine the scope of eligible research (Majumder and Cohen 2009, 195).

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The NIH issued draft guidelines for comment in April 2009 and published the final version of the guidelines in July 2009 (National Institutes of Health 2009). However, the NIH Guidelines are not the comprehensive guidelines for pluripotent stem cell research that many in the field had anticipated. They do not build upon or expand the NAS Guidelines. Instead, the NIH Guidelines focus on criteria for eligibility for NIH funding. Like earlier stem cell research guidelines, the NIH Guidelines confine eligibility to surplus embryos created for reproductive purposes through in vitro fertilization that are no longer needed for this purpose. To protect potential donors, the Guidelines stress the need for donors to provide voluntary written consent and require that potential donors be provided with information about all options available in the health care facility where treatment was sought as to the disposition of surplus embryos before consenting. Like the NAS Guidelines, the NIH Guidelines prohibit payments in cash or in kind for the donated embryos. The NIH Guidelines also repeat the NAS Guidelines’ requirement that policies and/or procedures are in place at the health care facility where the embryos were donated to assure that decisions to consent or refuse to donate embryos for research do not affect the quality of care. As another safeguard, the NIH Guidelines require that there be a clear separation between prospective donors’ decisions to create embryos for reproductive purposes and to donate human embryos for research purposes. To accomplish this goal, the Guidelines direct that decisions to create embryos for reproductive purposes should be free from the influence of researchers proposing to derive human embryonic stem cell lines from surplus embryos. The Guidelines further specify that consent for the donation be given at the time of donation even if the potential donors had previously indicated their intent to donate surplus embryos for scientific research. The Guidelines also have other requirements for the consent process. These include that the donors are informed that the embryos would be used to derive human embryonic stem cells for research and that the human embryonic stem cells derived from the embryos might be kept for many years. In addition, the Guidelines require that all donors not receive a direct benefit and that donations are made without restriction of the potential beneficiaries from the use of the human embryonic stem cells. Prospective donors additionally are to be told that, while the results of the research using the human embryonic stem cells may have commercial benefit, they would not share in it. There is also a section identifying what kinds of research are ineligible for NIH funding even when the cells may come from eligible sources. Some of these prohibited types of research overlap with the proscribed types of research in the NAS Guidelines. They include research

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in which pluripotent stem cells are introduced into non-human primate blastocysts and research involving the breeding of animals. The NIH Guidelines also repeat the prohibition, in earlier federal guidelines, of the use of NIH funding for the derivation of embryonic stem cell lines. All in all, what is not mentioned may be more notable than what is specified. In contrast with the NAS Guidelines, nothing is said about the need for an institutional stem cell research oversight committee to oversee NIH-funded research. The Guidelines do not provide any guidance for human embryonic stem cell research other than identifying types of research ineligible for funding. Nor do they discuss anything relating to human induced pluripotent stem cells. Dashing the hopes of some in the pluripotent stem cell field, the NIH Guidelines fail to create a national review committee or even a forum or process for addressing ethically complex new developments (Majumder and Cohen 2009, 198). To determine whether specific human embryonic stem cell lines meet the NIH eligibility requirements for research funding, the NIH created a stem cell review panel and established an online registry of its decisions. As of February 2020, 414 lines were listed as eligible, 33 were pending review, and 70 were listed as not approved, likely because the informed consent did not meet federal standards (National Institutes of Health 2020).

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The Role of the U.S. Food and Drug Administration (FDA) The mandate of the U.S. FDA is to ensure the safety and effectiveness of drugs, biological products, and medical devices as directed under the Biologics Control Act of 1902 and the Food, Drug, and Cosmetic Act of 1938. Although these statutes have been amended and modernized over time, they have been characterized as “still ‘remarkably ill fit’ for stem cell technology” (Margaret Foster Riley quoted in Institute of Medicine and National Academy of Sciences 2014, 26). In 1997 the FDA issued updated regulations requiring most human stem cell products to have premarket approval. The exceptions were those deemed minimally manipulated and used for autologous treatment. Thus far, the FDA has not recognized many products qualifying as minimally manipulated (Institute of Medicine and National Academy of Sciences 2014, 26). However, the FDA has also been reluctant to exercise its authority to shut down the more than 500 clinics dispensing unauthorized stem cell products in the U.S., many of which are more than minimally manipulated (Turner and Knoepfler 2016), possibly because it lacks sufficient staff to do so. Like the NIH and the Executive Branch, the FDA has also seemed reluctant to develop guidelines specifically

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addressed to cover pluripotent stem cell products. Recently, the FDA announced that it would develop a more consistent regulatory framework to govern stem cell and other regenerative medicine interventions, but thus far this has not happened (Maschke and Gusmano 2018, 5). The most relevant FDA statute with regulations applicable to stem cell–based products is the Public Health Safety Act, Section 361. The major objectives of this statute are “to prevent the use of contaminated tissue, limit the improper handling of tissues and ensure the clinical safety and efficacy of cells or tissues” (Halme and Kessler 2006, 1731). FDA regulations to determine the type, purity, and potency of stem cell–based products also applicable to pluripotent stem cell–based products include the following:

• Biologics regulation (21 CFR 600); • Section 361, Public Service Act addressing human cells, tissue, or cellular based products, 21 CFR 1271.3 (d);

• Section 351, Public Service Act, premarket approval, safety, and effectiveness of biologics, 21 CFR 600;

• Food, Drug, and Cosmetic Act, drugs, 21 CFR 200; • Application of Current Statutory Authorities to Human Somatic Cell Therapy Product and Gene Therapy Products, 14 October 1993;

• U.S. Public Health Service, Guideline on Infectious Disease Issues

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in Xenotransplantation, FDA 28, January 1997 (Slabiak 2012). The priorities of the FDA’s Center for Biologics, Evaluation and Research (CBER) are to enhance the translation of innovative science and technology into products for patients, advance regulatory science, and strengthen human resources and performance (Institute of Medicine and National Academy of Sciences 2014, 11). In 2008, the Center for Biologics, Evaluation and Research held a meeting devoted to human embryonic stem cell research. Prior to the meeting, it issued a briefing paper that stated that the purpose of the meeting was to provide the FDA with “insight and perspectives regarding safety concerns confronting development of cellular therapies derived from human embryonic stem cells” and to address the “characterization of [human embryonic stem cell] products, appropriate animal models for preclinical trials, and suitable monitoring for clinical studies” (Food and Drug Administration 2008, 1). The briefing document acknowledged that “the use of cellular products derived from [human embryonic stem cell]s present unique challenges worthy of further consideration” (Food and Drug Administration 2008, 8). It noted that earlyphase clinical trials of all cell therapies expose participants to potential risks that differ substantially from those associated with traditional Phase I drug

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trials. Those enumerated were that their pharmacological disposition is unpredictable; that unchecked proliferation is a real possibility in cellular products; and that the surgical procedures required for the administration of many cellular products may pose additional risks (Food and Drug Administration 2008, 8–9). The document also discussed the intrinsic capacity of human [embryonic stem cell]s to generate teratomas or tumors. In addition, the briefing paper cautioned that cell therapy products derived from human embryonic stem cells will be heterogeneous in their composition and may contain residual undifferentiated human embryonic stem cells and partially differentiated cells with the capacity to proliferate and differentiate further. It explained that these cells would have the ability to migrate from their target site of administration and possibly undergo inappropriate differentiation at a non-target site. While the members of the CTGTAC discussed these issues at their meeting, they did not draft guidelines, apparently because they thought the field was still too new (Food and Drug Administration 2008). Nevertheless, even in the absence of relevant guidelines, nine months after the CTGTAC meeting, the FDA approved the first clinical trial of an embryonic stem cell based therapeutic. At the end of 2016, then-President Barack Obama signed the 21st Century Cures Act into law, which is designed to bring high-priority products to market more quickly. The Cures Act has been described as a Faustian bargain that weakens safety requirements in drug and device regulations in order to expedite drug availability. Some analysts fear that it will do harm to patients. The passage of the law was attributed to massive lobbying by industry, which spent $192 million to promote enactment of the bill. The bill also had support from some academic centers, physician organizations, patient advocacy groups, and specialty societies (Kassirer 2018). The Cures Act provides for an accelerated approval pathway for therapies that qualify as Regenerative Medicine Advanced Therapies (RMAT). To be eligible, the therapy must be designed to treat a serious or life-threatening disease or condition and have preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for such a disease or condition. The FDA can then provide conditional approval, subject to the FDA post-approval requirements confirming the safety and efficacy of the therapy under conditions of actual use. The FDA also has the option of requiring additional clinical trials (Riley 2018, 298– 99). What this means is that some pluripotent stem cell–derived therapies designated as RMATs may be able to receive conditional FDA approval after completing Phase I and II clinical trials conducted on very small

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patient cohorts. Not having to conduct a Phase III trial requiring testing on a much larger cohort of patients, usually in a randomized double-blinded study design to compare outcomes in comparable groups of patients with one given the candidate therapy and the other treated with the current standard therapy or, if there is none, a placebo – will save time and money. But is it safe to do so? According to one legal and medical expert in the stem cell field, given the state of knowledge, bypassing a Phase III study as is permitted by the Cures Act may be dangerous and may stymie the overall development of the regenerative medicine field rather than facilitate it (Riley 2018, 304). Much will depend on the way the FDA implements the provisions of the Cures Act. As of December 2019, the FDA had received 115 requests and given 44 candidate therapies RMAT designation. Two of the therapies, Asterias Biotherapeutics’ investigational therapy for spinal cord injury and jCyte’s therapy for retinitis pigmentosa, are derived from human embryonic stem cells (Hildreth 2019). Others are also stem cell products. But information on one of these products, Oxbryta, which is a drug (not a stem cell–based therapy) for sickle cell disease, is concerning. The approval was made on the basis of a single clinical trial involving 274 participants of whom 90 received the candidate therapy at one dose level, 92 received the therapy at another dose level, and the remainder received a placebo. The sponsor is required to conduct additional trials to verify and describe the clinical benefit, but the product will be able to be marketed during this period (U.S. Food & Drug Administration 2019).

State-Level Stem Cell Regulation in the United States Stem cell research policy in the United States is set at both federal and state levels, resulting in a potentially conflicting patchwork of policies. The Bush-era policies and their restrictions drew several states into the stem cell arena, some to develop funding programs that bypassed the restrictions in the Bush policies and others to impose additional restrictions. The State of California stands at the forefront of the field with its $3 billion of funding dedicated to stem cell research, made available through the passage of Proposition 71 in 2004 and the establishment of the California Institute for Regenerative Medicine (CIRM) to set policies, disburse funds, and oversee the research. CIRM has developed the most comprehensive state-level regulatory structure for stem cell research. The specifics of California state regulations and the CIRM operating structure will be discussed in Chapter Five. Several other states – New Jersey, Massachusetts, Connecticut, Maryland, Missouri, and New York – passed legislation to authorize and

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regulate stem cell research between 2002 and 2006, possibly encouraged by the presence in state of large research universities and active biotechnology industries. The foundational concepts of the legislation in these states are the legalization of embryonic stem cell research, the prohibition on reproductive cloning, the requirement that gametes or embryos be donated only with full informed consent of the donors, and the requirement that dedicated oversight mechanisms be in place in each institution undertaking this research. The level of funding for embryonic stem cell research has varied, but in all of these states funding pluripotent stem cell research it has been a fraction of California’s investment. Several other states, including Michigan and Iowa, have adopted legislation confirming the legality of stem cell research without appropriating funds for this purpose.

Stem Cell Regulation in Other Countries

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The UK Code of Practice for the Use of Human Stem Cell Lines The UK has a multi-layered regulatory system for human stem cell lines, particularly for human embryonic stem cell lines. In the UK, all research involving human embryos, including the generation of human embryonic stem cell lines, is under the statutory authority of the Human Fertilisation and Embryology Authority (HFEA). Once established, embryonic stem cell lines are not considered to be embryos and therefore are not subject to the same level of regulation that the HFEA applies to embryo research. Institutional oversight in the form of a Steering Committee for the creation of new stem cell lines is recommended to ensure ethical practices, as is adherence to the UK Code of Practice for the Use of Human Stem Cell Lines. Although both provisions are voluntary, they are HFEA licensing requirements. The UK Code of Practice for the Use of Human Stem Cell lines applies to all research involving established human embryonic stem cell lines, since their generation involves the destruction of human embryos. Other types of pluripotent stem cell lines, such as those developed through induced pluripotency, fall outside the Code of Practice even when ethical considerations remain regarding their derivation and use (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, Foreword). Embryonic stem cell lines derived in the UK are subject to the donor consent requirements of the HFEA, including those relating to donor anonymity (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 4.1). To apply for a research license involving embryonic stem cells, scientists must first apply for ethical approval from one of the local research

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ethics committees set up by the Department of Health. Because these committees consider a wide range of research applications in all areas of health research, it can take over six months to obtain approval. The HFEA also sends out all research license applications to conduct its own peer review. This process can take over a year. An application for grant support by one of the UK’s research councils, a primary source of funding for stem cell research, will only be considered once HFEA approval has been secured (Winston 2007, 33). In addition, all UK researchers deriving human embryonic stem cell lines are required to deposit samples of their lines in the UK Stem Cell Bank. Doing so is optional for induced pluripotent stem cell lines and somatic cell lines. The UK Stem Cell Bank stores and distributes stem cell lines. Ownership, including intellectual property in these lines, remains with the originator (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para 4). A Steering Committee for the UK Stem Cell Bank and for research involving use of stem cell lines was established in 2002. The role of the Steering Committee is to support stem cell research and to ensure that it is conducted within an ethical framework that is transparent to the public. Its membership includes expertise in science, medicine, ethics, and theology along with lay members and representatives from regulatory and funding agencies (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 5.1). The Steering Committee requires that human embryonic stem cell lines are used by bona fide research groups for justified and valuable purposes such as research that increases knowledge about the development of embryos or has the long term goal of helping to increase knowledge about serious diseases and their treatment, basic cell research which underpins these aims, and the development of cell based therapies for clinical trials to address serious human diseases (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 7.1.1). Although the Steering Committee considers the UK Stem Cell Bank to be the preferred source of stem cell lines, researchers may access lines from other sources whose lines are ethically sourced with fully informed and free donor consent (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 7.2). Clinical trials of stem cell–based products in the UK are authorized and regulated by the Medicines and Healthcare Products Regulatory Agency (MHRA) (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 3.4). In addition, the Gene Therapy Advisory Committee (GTAC) has responsibility for the ethical oversight of proposals to conduct gene therapy or stem cell therapies derived from stem

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cell lines (Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines 2010, para. 3.6).

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Regulation of Stem Cell Research in Japan In Japan, biomedical research is divided into basic and clinical research. The former is regulated by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the latter by the Ministry of Health, Labor and Welfare (MHLW). In 1998, the Government established a Bioethics Committee under the Prime Minister. It presented a report in 2000 on human embryonic stem cell research, and, following that report, guidelines on the derivation and use of human embryonic stem cell lines were issued in 2001. The guidelines set forth standards for the derivation of human embryonic stem cells, including regulations on the donation and use of human embryos and on their domestic distribution. They allowed scientists to derive new human embryonic stem cell lines and to conduct their research with both domestic and imported cell lines. Proposed projects needed to be approved on two levels, first by a local institutional review board and then by a science-ministry committee, and the process was very slow (Cyranoski 2009). The first three human embryonic stem cell lines were derived in 2003. In 2006, the MHLW issued ethical guidelines on the use of human adult stem cells in clinical trials (Ida 2010, 919–22). Japanese scientists have been reluctant to bypass ministry guidelines, even though the guidelines do not have the force of law, because there are limited sources of funding in Japan other than the government (Kawakami, Sipp, and Kato 2010). In 2009, the guidelines on human embryonic stem cells were amended to simplify the process. Under the amended guidelines, approval by a local review committee was still required, but researchers only had to notify the science ministry. The two-stage approval process was left in place for deriving new embryonic stem cell lines. The cumbersome rules for human embryonic stem cell research and the availability of targeted funding programs to encourage involvement in induced pluripotent stem cell research, which was first developed by the Japanese scientist Shinya Yamanaka, pushed most of Japan’s stem cell researchers into working with induced pluripotent cell research (Cyranoski 2009). In late 2014, in an effort to move to the cutting edge of research and clinical applications in regenerative medicine, and especially of the development of induced pluripotent stem cell–based therapies, Japan relaxed its stem cell regulatory regime. Japan adopted a new law intended to accelerate the approval of regenerative therapies and the commercialization

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of cell therapies within the country by providing an accelerated conditional approval pathway for stem cell therapies. To qualify, a therapy must address an unmet medical need for a serious disease or chronic debilitating condition. Under the new framework, a product can be approved based on preliminary data confirming safety with predicted, but not proven, indications of efficacy. Pivotal confirmatory trials can take place after the product is made available to patients in Japan. This means that a conditional marketing authorization may be granted without the need for high-powered and expensive Phase 3 clinical trials. Following approval, there will be a post-market surveillance period of five to seven years to evaluate the product for safety and efficacy. In Japan, national insurance reimbursement is applied to regenerative medical products granted conditional approval. However, patients using these conditionally approved therapies have to contribute the 30 percent co-pay generally required under Japan’s national insurance plan, and the money will not be reimbursed if the therapies are not effective (Sietsema et al. 2018). As of May 2019, three new regenerative medicine products had been approved, all on the basis of small, single-arm clinical trials conducted in Japan. Conditional approval for all three products is valid for five or seven years. Approval for one of these, a product for heart failure caused by ischemic heart disease, was based on a clinical trial with only seven patients plus a modicum of supportive data (Sietsema et al. 2018). In the treatment, the patients received a sheet of muscle cells made from their own leg muscles. To receive final approval, the company marketing and selling the treatment must provide data from at least 60 patients treated with the therapy and 120 controls to show the treatment is effective. This seems unlikely to happen. So far, the researchers have found the therapy to be ineffective, especially for more serious cases, and some physicians have called for the tests to end. A new induced pluripotent stem cell study by the same researcher with the same goals is set to begin (Nature Editorial Board 2015, 2018). The second product issued a conditional approval, a stem cell biologic for the treatment of spinal cord injury, also sparked controversy, as it was based on a single, small, uncontrolled, and unpublished study (Sipp and Sleeboom-Faulkner 2019). The third regenerative medicine product, STEMIRAC, targets neurological symptoms and functional disorders associated with spinal cord injury, and its conditional approval was also based on a small study, this time of only 17 patients (Nagai 2019, 7). Then, in 2019, Japan gave market approval to a spinal cord injury treatment ostensibly based on a mesenchymal stem cell. The very nature of these cells, in particular whether they function as stem cells and do indeed turn into neurons, is the subject of debate. The clinical trials that demonstrated

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efficacy were based on only 13 participants and had no control group. As in Japan’s other accelerated approvals, the trial data remain unpublished (Nature Editorial Board 2019). Critics have raised concerns as to whether the 2014 Japanese regenerative medicine law can assure safety and efficacy. Some have characterized it as too permissive (Knoepfler 2018). One issue is whether post-market surveillance without controls will turn up relevant data (Cyranoski 2013). Two editorials in Nature have stated that the rules are not adequate or appropriate and do not have the welfare of patients at their heart. Nature has warned, “Japan could find itself flooded with unsuccessful treatments” (Nature Editorial Board 2015). Japan’s desire to be at the forefront of the regenerative medicine field and to use induced pluripotent stem cells as a new engine of economic growth does not warrant adopting laws that place patients at risk. As Nature magazine commented, “The country shouldn’t sell short the promising technology or the patients who hope to benefit from it” (Nature Editorial Board 2018, 612). Unfortunately, in an international context, regulatory changes providing a short-term economic advantage in one country can have a cascading effect, leading to detrimental consequences. Regulators and policy makers in several other countries have responded to Japan’s new regulatory regime as giving the country a competitive challenge they should seek to emulate. Korea had earlier adopted a preferential regulatory treatment for stem cell medicine that then encouraged Japan to do likewise. A Regenerative Medicine Group convened by the UK government identified the Japanese law as placing the UK at a competitive disadvantage. The Japanese example also encouraged the drafting of the provisions of the 21st Century Cures Act in the U.S. that provided for accelerated review and approval of regenerative medicine products (Sipp and Sleeboom-Faulkner 2019).

The International Society for Stem Cell Research’s Guidelines The International Society for Stem Cell Research (ISSCR) has issued three sets of guidelines for stem cell research and applications. Founded in 2002 to provide a forum for communication and education in the emerging fields of stem cell research and regenerative medicine, ISSCR is the most significant international professional organization engaged with stem cell research. ISSCR developed Guidelines for the Conduct of Human Embryonic Stem Cell Research in 2006 and Guidelines for the Clinical Translation of Stem Cells two years later. In 2016, ISSCR published

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updated and much-expanded guidelines, particularly in the sections on clinical trials. These latter Guidelines are the most comprehensive and ethically informed guidelines for pluripotent stem cell research currently available.

2006 ISSCR Guidelines for the Conduct of Human Embryonic Stem Cell Research Compared with later iterations of ISSCR guidelines, the 2006 edition is quite preliminary. The topics and content follow the recommendations of the National Academy of Science guidelines, and the document acknowledges that it borrows extensively from the principles and language of that document as well as from the Medical and Ethical Standards Regulations of the California Institute for Regenerative Medicine (International Society for Stem Cell Research 2006).

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2008 ISSCR Guidelines for the Clinical Translation of Stem Cells The 2008 Guidelines for the Clinical Translation of Stem Cells were developed by a multidisciplinary task force of stem cell researchers, clinicians, ethicists, and regulatory officials from 13 countries. According to its preface, the Guidelines “highlight the scientific, clinical, regulatory, ethical, and social issues that should be addressed so that basic stem cell research is responsibly translated into appropriate clinical applications for treating patients” (International Society for Stem Cell Research 2008). This version of the ISSCR guidelines is far more comprehensive than the earlier 2006 publication. The 2008 Guidelines address three major areas of translational stem cell research: (1) cell processing and manufacture, (2) preclinical studies, and (3) clinical research. Some of its recommendations address the need for stringency in the peer review process for stem cell research and clinical studies. It also considers aspects of cell processing and manufacture, including requirements for permission of donors, screening of donors for infectious diseases, and the replacement of components of animal origin with human components whenever possible to reduce the risk of accidental transfer to patients of unwanted biological material or pathogens (International Society for Stem Cell Research 2008, recommendations 3, 4, and 5). The relevance of this last requirement is that, at the time these guidelines were published, most human embryonic stem cell lines were cultured on mouse feeder layers. This is no longer the case. ISSCR also advised that sufficient preclinical studies in relevant animal models – matched whenever possible for the clinical condition and tissue physiology

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to be studied – are necessary for proposed stem cell–based clinical research to be ethical. The 2008 Guidelines break new ground with recommendations for the regulatory review and oversight of clinical trials. According to the Guidelines, all studies involving clinical applications of stem cells, regardless of the type of sponsorship, must be subject to independent review, approval, and ongoing monitoring by human subjects research oversight bodies with appropriate expertise to evaluate the unique aspects of stem cell research (International Society for Stem Cell Research 2008, recommendation 21). The Guidelines advise that the peer review process for stem cell–based clinical trials should be by individuals who have appropriate expertise to evaluate the in vitro and in vivo clinical studies that form the basis for proceeding to a clinical trial. In addition, they should also be able to assess the scientific underpinnings of the trial protocol and the adequacy of planned end points of analysis (International Society for Stem Cell Research 2008, recommendation 22). The Guidelines also address the appropriate standards for voluntary informed consent, noting that informed consent is particularly challenging for clinical trials involving highly innovative interventions (International Society for Stem Cell Research 2008, recommendation 28). Notably, the 2008 Guidelines also address issues of social justice, as do the 2016 updated and expanded Guidelines. As the Guidelines explain, ethical arguments in support of stem cell research depend in part on the potential for advancing scientific knowledge that may result in therapies or cures for disease and other health benefits. Therefore, governments, institutions, researchers, and providers involved with the field have a responsibility to address issues of public benefit as well as to ensure that these therapies and benefits are justly available. According to the Guidelines, considerations of social justice also extend to choosing which applications to address for clinical development (International Society for Stem Cell Research 2008, recommendation 11). In a field where animal testing was and still is conducted predominantly in rodent models, the guidelines recommend that large animal models should be used for stem cell research related to diseases that cannot be adequately studied using small animal models but do not provide criteria for this determination (International Society for Stem Cell Research 2008, recommendation 14). The Guidelines suggest that the need for studies in non-human primates should be evaluated on a case-by-case basis and approved only if the studies will provide necessary and otherwise unobtainable information (International Society for Stem Cell Research 2008, recommendation 15). The guidelines stress that risks for tumorigenicity must be assessed for any

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stem cell-based product, particularly when it is extensively manipulated in culture or genetically modified (International Society for Stem Cell Research 2008, recommendation 18). It appears that the 2008 edition of the guidelines was prompted, at least in part, by a concern with newly opened clinics around the world exploiting patients’ hopes by offering stem cell therapies “without credible scientific, rationale, transparency, oversight, or patient protections” (Hyun et al. 2008). The Guidelines state that “The ISSCR is deeply concerned about the potential physical, psychological, and financial harm to patients who pursue unproven stem cell–based ‘therapies’ and the general lack of scientific transparency and professional accountability of those engaged in these activities” (International Society for Stem Cell Research 2008, 4). To counter patients’ unrealistic expectations, the Guidelines advise that “The public, too, should recognize that in all areas of medicine, the maturation of an early-phase experimental intervention into an accepted standard of medical practice is a long and complex process usually involving many years of rigorous preclinical and clinical testing and many setbacks and failures” (International Society for Stem Cell Research 2008, 4). The Guidelines also stress that stem cells and their direct derivatives represent, in most cases, an entirely novel product complicating their design and development. Additionally, the Guidelines advise that animal models of many diseases do not accurately reflect the human diseases they model and, as a consequence, toxicological studies in animals may be poor at predicting toxicity in humans or unable to predict biological responses in patients (International Society for Stem Cell Research 2008, 4). To enable individuals and their doctors to make better choices, the Guidelines include a patient guide in an Appendix.

2016 ISSCR Guidelines for Stem Cell Research and Clinical Translation The ISSCR’s 2016 Guidelines for Stem Cell Research and Clinical Translation were developed by an international task force of 25 leading stem cell scientists and ethicists having extensive experience with stem cells. Draft guidelines were posted for a three-month period of public comment to encourage review and input by others in the stem cell community before they were finalized. The task force also sought perspectives from individuals within regulatory authorities, funding agencies, industry, patient advocacy organizations, and professional societies (International Society for Stem Cell Research 2016, Preface). The

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2016 ISSCR guidelines update and considerably expand ISSCR’s earlier iterations. The Guidelines identify five guiding principles: the integrity of the research enterprise, the primacy of patient welfare, respect for research participants, the need for transparency, and the importance of social justice. According to the Guidelines, the primary goals of stem cell research are to advance scientific understanding and to generate evidence for addressing medical and public health needs. To ensure the integrity of the research enterprise, in order to maintain public confidence and ensure the data will be reliable and accessible, the Guidelines state that research should be overseen by qualified investigators through independent peer review and oversight processes with replication at each stage of research. The Guidelines explain that the primacy of patient welfare means that physicians and researchers owe primary duty to patients and/or research subjects and therefore must never unduly place vulnerable patients or subjects at risk. Respect for research participants, according to the guidelines, requires that human subjects can exercise valid informed consent when they have adequate decision-making capacity. Transparency entails researchers making accurate scientific information available to interested parties, including patient communities (International Society for Stem Cell Research 2016 Guidelines, Section 1, p.5). The guideline on social justice is particularly notable because few other treatments of the translation of scientific discoveries include a discussion of social justice. According to the Guidelines, the benefits of clinical translation efforts should be distributed justly and globally, with a particular emphasis on addressing unmet medical and public health needs. To do so, the Guidelines recommend that advantaged populations should seek to share benefits with disadvantaged populations and that trials should strive to enroll populations diverse in age, sex, and ethnicity. Like other proponents of inclusiveness, the Guidelines state that social justice requires that trials should strive to include women as well as men and members of racial and ethnic minorities. The Guidelines specifically caution that burdens associated with clinical translation should not be borne by populations who are unlikely to benefit from the knowledge produced in these efforts. In addition, the Guidelines recommend that new products should not be approved for routine clinical use without a favorable balance of risk and benefit being shown by their clinical trials. The Guidelines also stress that developers should strive to maximize access to treatments (International Society for Stem Cell Research 2016 Guidelines, Section 1, p.5). In another section, dealing with access and economics, the Guidelines affirm that research, clinical, and commercial activities should seek to

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maximize affordability and accessibility (International Society for Stem Cell Research 2016 Guidelines, Section 3.5.2, p. 26-27). However, the Guidelines do not go so far as to recommend that publicly funded stem cell research should require that products developed from the stem cell research be available on an affordable basis, particularly to disadvantaged patient populations. I think this is a shortcoming. It is difficult to know how influential the ISSCR guideline on social justice has been.

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Reflections The introduction to this chapter noted that scientific research and its ethical translation into clinical therapies require explicit guidelines, regulations, and oversight mechanisms to inform and guide the work that preferably are informed by explicit ethical principles and norms. This is especially important given the novelty and unpredictability of early-stage human pluripotent stem cell research and its ethical sensitivity. The role of guidelines and/or regulations is to encourage research institutions and researchers to develop and adopt the best practices for the ethical conduct of research as well as to reassure the public that the research is being conducted ethically and responsibly. However, designing these guidelines and regulations for a new area of medical research, particularly for such an innovative field, presents significant challenges. So, how much progress has there been in meeting these important goals? This chapter indicates that, twenty plus years into the development of the pluripotent stem cell field, the guidelines and regulations for the field are for the most part incomplete. This is particularly the case in the United States, which lacks federal regulations to inform pluripotent stem cell research that would assure uniformity in research practices and oversight. Moreover, there is no federal oversight body to review new applications and oversee clinical trials on the model of the RAC. The initial 2006 stem cell guidelines from the National Academy of Sciences (NAS) are incomplete in the topics covered and their application is voluntary. Of the guidelines that have been proposed, ISSCR’s are by far the best. Its 2008 and 2016 guidelines proceed from explicit ethical principles. They are the only guidelines that do so. The ISSCR’s 2016 guidelines are particularly comprehensive, covering a wide range of topics related to research and translation, including detailed guidelines for clinical trials. However, the guidelines were issued well after many of the institutions conducting human pluripotent stem cell research had already set their policies. Also, like NAS’s guidelines, ISSCR’s guidelines lack official status. It is unknown

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how many research institutions have adopted ISSCR’s guidelines in part or in full or will do so in the future. Two recent regulatory initiatives to accelerate progress in the regenerative medicine field are worrying. The 2016 U.S. Cures Act will enable high-priority pluripotent stem cell–based therapies to be reviewed and approved by the FDA on an expedited basis that presumably will not require full Phase 3 clinical trials. Similarly, the 2014 Japanese regenerative medicine law provides for pluripotent-based stem cell therapies to obtain conditional approval and proceed to market based on Phase I or II clinical trials with small patient cohorts. Both accelerated pathways for regenerative medicine products are extremely problematic. Pluripotent stem cell–based products are innovative, largely untested, and high-risk. Many of the patients seeking pluripotent stem cell treatments will be seriously ill. Most of these therapies will be first-in-human therapies without comparable studies enabling regulators to anticipate problems. A January 2019 editorial in Nature magazine, responding to what it termed Japan’s unwise step to commercialize unproven stem cell therapies, recommended that unproven therapies not be marketed to patients (Nature Editorial Board 2019). I agree with that recommendation. In 2009, gene therapy researcher James Wilson, who had directed an early gene therapy clinical trial that resulted in the death of 18-year-old Jesse Gelsinger and set back the gene therapy field for many years, published an essay. In it, he urged researchers working on human embryonic and induced pluripotent stem cells not to repeat gene therapy’s mistake of rushing to clinical trials (Wilson 2009). However, pluripotent stem cell researchers have proceeded to clinical trials seemingly as soon as possible, and now regulators in Japan and the U.S. can permit new regenerative medicine therapies to proceed to market without first undergoing the full three stages of clinical testing. Accelerating availability at the expense of safety and patient protection is ethically unjustified. Regulators should make certain that new stem cell- based therapies are fully tested and have valid claims to safety and efficacy before they are made available to patients.

References Brewer, C. D., and Heather DeGrote (2013) “Justifying Tomorrow’s Escros.” The American Journal of Bioethics 13 (1): 65–66. Chapman, Audrey R. (2013) “Evaluating Escros: Perspectives from the University of Connecticut.” The American Journal of Bioethics 13 (1): 57–58.

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Cohen, Cynthia B. (2007) Renewing the Stuff of Life: Stem Cells, Ethics, and Public Policy. Oxford, UK: Oxford University Press. Cohen, Cynthia B., and Mary A. Majumder (2009) “Future Directions for Oversight of Stem Cell Research in the United States.” Kennedy Institute of Ethics Journal 19 (1): 79–103. Cyranoski, David (2009) “Japan Relaxes Human Stem-Cell Rules.” Nature 460 (7259): 1068. https://www.nature.com/articles/4601068a. Cyranoski, David (2013) “Japan to Offer Fast-Track Approval Path for Stem Cell Therapies.” Nature Medicine 19 (5): 510. https://www.nature.com/articles/nm0513-510. Devereaux, Mary, and Michael Kalichman (2013) “ESCRO Committees— Not Dead yet.” The American Journal of Bioethics 13 (1): 59–60. Ellison, Brooke (2013) “Making Escro Committees Work in New York.” The American Journal of Bioethics 13 (1): 63–64. Food and Drug Administration (2008) “CTGTAC Meeting # 45: Cellular Therapies Derived from Human Embryonic Stem Cells – Considerations for Pre-Clinical Safety Testing and Patient Monitoring” (Internet Archive, captured January 26, 2018). http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-0471B1_1.pdf. Greely, Henry T. (2013) “Assessing Escros: Yesterday and Tomorrow.” The American Journal of Bioethics 13 (1): 44–52. Halme, Dina Gould, and David A. Kessler (2006) “FDA Regulation of Stem-Cell–Based Therapies.” New England Journal of Medicine 355 (16): 1730–5. Hildreth, Cade (2019) “What Is an Rmat? List of Rmat Designations.” BioInformant (Accessed 23 May 2020). https://bioinformant.com/rmat/. Hyun, Insoo, Olle Lindvall, Lars Ährlund-Richter, Elena Cattaneo, Marina Cavazzana-Calvo, Giulio Cossu, Michele De Luca, et al. (2008) “New Isscr Guidelines Underscore Major Principles for Responsible Translational Stem Cell Research.” Cell Stem Cell 3 (6): 607–9. Ida, Ryuichi (2010) “Stem Cell Policies and Regulations in Japan.” Singapore Academy of Law Journal 22: 919–30. Institute of Medicine and National Academy of Sciences (2014) Stem Cell Therapies: Opportunities for Ensuring the Quality and Safety of Clinical Offerings: Summary of a Joint Workshop. Washington, DC: The National Academies Press (Rapporteurs: Adam C. Berger, Sarah H. Beachy, and Steve Olson). Institute of Medicine and National Research Council (2005) Guidelines for Human Embryonic Stem Cell Research. Washington, DC: The National Academies Press.

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Institute of Medicine and National Research Council (2008) 2008 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research. Washington, DC: The National Academies Press. International Society for Stem Cell Research (2006) Guidelines for the Conduct of Human Embryonic Stem Cell Research. https://www.isscr.org/docs/default-source/all-isscr-guidelines/hescguidelines/isscrhescguidelines2006.pdf. International Society for Stem Cell Research (2008) Guidelines for the Clinical Translation of Stem Cells. https://www.isscr.org/docs/defaultsource/all-isscr-guidelines/clin-trans-guidelines/isscrglclinicaltrans.pdf. International Society for Stem Cell Research (2016) Guidelines for Stem Cell Science and Clinical Translation. http://www.isscr.org/guidelines2016. Interstate Alliance on Stem Cell Research (2011) “Survey of Escro Committees: Overview.” Interstate Alliance on Stem Cell Research. http://nas-sites.org/iascr/files/2013/08/ESCRO2011.pdf. Kahn, Jeffrey P., and Anna C. Mastroianni (2018) “Sunset on the Rac: When Is It Time to End Special Oversight of an Emerging Biotechnology?” The American Journal of Bioethics 18 (12): 1–2. Kassirer, Jerome P. (2018) “The 21st Century Cures Potpourri: Was It Worth the Price?” American Journal of Law & Medicine 44 (2-3): 157– 60. Kawakami, Masahiro, Douglas Sipp, and Kazuto Kato (2010) “Regulatory Impacts on Stem Cell Research in Japan.” Cell Stem Cell 6 (5): 415–18. Knoepfler, Paul (2018) “Japan Stem Cell Oversight System Too Lax?” The Niche: Knoepfler Lab Stem Cell Blog, May. https://ipscell.com/2018/05/japan-stem-cell-oversight-system-too-lax/. Lomax, Geoffrey (2013) “The Great Escro Experiment: There Is Still Value to Be Gained.” The American Journal of Bioethics 13 (1): 55–56. Majumder, Mary A., and Cynthia B. Cohen (2009) “Future Directions for Oversight of Stem Cell Research in the United States: An Update.” Kennedy Institute of Ethics Journal 19 (2): 195–200. Maschke, Karen J., and Michael K. Gusmano (2018) Debating Modern Medical Technologies: The Politics of Safety, Effectiveness, and Patient Access. Santa Barbara, CA: ABC-CLIO. Nagai, Sumimasa (2019) “Flexible and Expedited Regulatory Review Processes for Innovative Medicines and Regenerative Medical Products in the Us, the Eu, and Japan.” International Journal of Molecular Sciences 20 (15).

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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 Institutes of Health (2001) Notice of Criteria for Federal Funding of Research on Existing Human Embryonic Stem Cells and Establishment of Nih Human Embryonic Stem Cell Registry. National Institutes of Health. 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 (2020) “Stem Cell Registry.” https://grants.nih.gov/stem_cells/registry/current.htm. Nature Editorial Board (2015) “Stem the Tide: Japan Has Introduced an Unproven System to Make Patients Pay for Clinical Trials.” Nature 528 (7581): 163–64. https://www.nature.com/news/stem-the-tide-1.18976. Nature Editorial Board (2018) “Stem-Cell Tests Must Show Success: Japan Needs to Demonstrate That a Promising Therapy for Damaged Hearts Works as Claimed.” Nature 557 (May): 611–12. https://www.nature.com/articles/d41586-018-05284-w. Nature Editorial Board (2019) “Japan Should Put the Brakes on Stem-Cell Sales.” Nature 565 (January): 535–36. https://www.nature.com/articles/d41586-019-00332-5. Riley, Margaret F. (2018) “A Rat by Another Name: 21st Century Cures Act and Stem Cell Therapies.” American Journal of Law & Medicine 44 (2-3): 291–308. Sietsema, William K., Yoshiyuki Takahashi, Kosuke Ando, Tetsuro Seki, Atsuhiko Kawamoto, and Douglas W. Losordo (2018) “Japan’s Conditional Approval Pathway for Regenerative Medicines.” Regulatory Focus, May. Sipp, Douglas, and Margaret Sleeboom-Faulkner (2019) “Downgrading of Regulation in Regenerative Medicine.” Science 365 (6454): 644–46. Slabiak, Trina (2012) “Stem Cell-Based Therapies and FDA Regulations.” Regulatory Focus, November. Steering Committee for the UK Stem Cell Bank and for the Use of Stem Cell Lines (2010) Code of Practice for the Use of Human Stem Cell Lines (version 5). Medical Research Council, UK Research and Innovation. https://mrc.ukri.org/documents/pdf/code-of-practice-for-the-use-ofhuman-stem-cell-lines/.

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Turner, Leigh, and Paul Knoepfler (2016) “Selling Stem Cells in the Usa: Assessing the Direct-to-Consumer Industry.” Cell Stem Cell 19 (2): 154–57. U.S. Food & Drug Administration (2019) “FDA Approves Novel Treatment to Target Abnormality in Sickle Cell Disease.” News release (Accessed 23 May 2020). https://www.fda.gov/news-events/press-announcements/ fda-approves-novel-treatment-target-abnormality-sickle-cell-disease. Wilson, James M. (2009) “A History Lesson for Stem Cells.” Science 324 (5928): 727–28. Winston, R. M. L. (2007) “Does Government Regulation Inhibit Embryonic Stem Cell Research and Can It Be Effective?” Cell Stem Cell 1 (1): 27– 34.

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CHAPTER FOUR

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CHALLENGES IN THE TRANSLATION OF PLURIPOTENT STEM CELL RESEARCH INTO THERAPIES

All biomedical research is complex. Translation of that research into clinical therapies is even more so. Moreover, the development of stem cell therapies, particularly pluripotent stem cell candidate therapies, is substantially more complex than the chemically based small-molecule drugs that have hitherto dominated biomedical research and the development of therapies. Pluripotent stem cell–based therapies that are currently under development are novel products with little therapeutic history in human subjects. Also, 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” (2013, 50). Moreover, while most small-molecule drugs are developed by companies with extensive experience manufacturing pharmaceuticals and are regulated by the FDA or a comparable regulatory body based on established protocols, the situation is quite different for cell-based therapeutics. Most pluripotent stem cell–based products originate in academic laboratories or small biotechnical companies that are likely to have limited experience in developing manufacturing processes or running clinical trials (Hyun 2013, 50). All of this means there are likely to be longer developmental timelines and greater risks in the translation of pluripotent stem cell research into marketable therapies compared with the experience of the pharmaceutical industry. In a 2012 article, Francis Collins, the Director of the NIH, and Mahendra Rao, the first Director of the NIH Intramural Center of Regenerative Medicine, identified ten roadblocks affecting the translation of stem cell therapies: 1. Periods of limited government involvement due to legal, political and ethical issues

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Chapter Four 2. Lack of mature regulatory policy 3. Absence of uniform regulations and activity across countries 4. Absence of uniform global patent interpretations on pluripotent stem cells 5. Absence of standards and controls 6. Lack of successful business models thus far for autologous therapy 7. Limited availability of investment in new business models 8. Issues of consent and sourcing related to cell-based manufacture 9. Limited expertise in scaled-up cell manufacturing 10. Issues of risk management, reimbursement, and long-term follow-up in cell-based therapy trials (Rao and Collins 2012).

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Some of these issues are addressed at least in part in other chapters of this book: the limited government involvement in Chapters One and Three, the lack of mature regulatory policy in Chapter Three, questions regarding long-term patient follow-up in Chapter Six, and patenting policies in Chapter Eight. This chapter will focus on four sets of challenges: The first regard the implications for the translation of stem cells into therapies of the lack of a well-defined and comprehensive regulatory framework. The second relate to problems of securing sufficient funding for pluripotent stem cell research and clinical trials. The third are issues of cell processing and manufacturing required to meet the standards necessary for human applications. The final set of challenges are the widespread availability of unauthorized stem cell therapeutics and what it means for the welfare of patients and for the reputation and standing of the stem cell industry.

Implications of the Lack of a Well-Defined Regulatory Framework for Pluripotent Stem Cell Translation The previous chapter documented the lack of an official comprehensive regulatory framework for pluripotent stem cell research. This means that researchers and sponsors have to navigate an evolving and uncertain regulatory environment for the translation of products and for clinical trials with pluripotent stem cells. A 2010 article characterized the situation as follows: “Unlike for biologics and small molecules, the regulatory pathway for stem cell-derived therapeutics is not well defined, and hence, not well understood” (Trounson et al. 2010, 514). The article goes on to note, “While the biologic and small molecule industries benefit from a well-defined regulatory pathway and commonly accepted best practices for preclinical safety testing, product characterization, and measures of purity and potency, the same cannot be said for product development for the stem cell industry” (Trounson et al. 2010, 514). The situation has not changed in the past ten

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years. The failure of the FDA to develop regulations specific to pluripotent stem cells has meant that the FDA has had to struggle to apply regulations tailored to other, very different types of drugs to candidate pluripotent stem cell therapeutics. This problem has contributed to long timelines and uncertainty. The situation is further complicated by the lack of familiarity with the highly regulated requirements for product development in the academic stem cell research community, where much of the stem cell knowledge base resides (Trounson et al. 2010, 515). Many in the stem cell industry complain about the difficulty and the length of time needed to move a candidate stem cell treatment through preclinical development and into clinical trials. According to a study done by the California Institute for Regenerative Medicine (CIRM), the average time necessary for traditional pharma and biotech drugs is 3.2 years. In comparison, it is 8 years for stem cell treatments. CIRM attributes this delay to a number of reasons. First, the FDA has applied the drug development model for conventional drugs to stem cell treatments, “which is like forcing a round peg into a square hole” (California Institute for Regenerative Medicine, n.d., 9). Second, the scope of studies required is extensive and optimal study designs are not well-defined by regulatory agencies. Third, a lack of familiarity among investigators with the requirements for IND approval lengthens the time for a successful filing (California Institute for Regenerative Medicine, n.d., 9). The situation is sufficiently problematic that, in a survey conducted by CIRM of its board members, researchers in the field, and patient advocates, 70 percent of respondents identified the FDA as the biggest impediment for the development of stem cell treatments (California Institute for Regenerative Medicine, n.d., 10). This is quite an indictment of the FDA. These problems then contribute to the inability to raise sufficient funding for cell manufacturing and trials.

Funding for Pluripotent Stem Cell Translation Translation of basic research into therapies is an expensive process, far more so than the research. New technologies require sufficient financial resources, preferably long-term investments, to fund development of the therapeutics, establishment of manufacturing processes consistent with the stringent purity and quality requirements for human applications, sponsorship of the three stages of clinical trials needed for regulatory approval, and navigation through the regulatory process. On average, the development of a new medicine from initial preclinical research to market approval takes ten years and may cost up to $1.2 billion. While these challenges are not unique to stem cell therapies, the novelty of stem cell–

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based interventions, particularly of pluripotent stem cell–based therapies, complicates them. The financial challenges that cell therapy development faces are exacerbated by the scientific and policy challenges associated with the field (Dodson and Levine 2015). Industry and venture capitalists have hesitated to invest, considering it too risky, until the developers can provide additional demonstrations of success. Public funding is often too limited to cover the long path to translation (Rosemann 2014, 2074). Ethical and religious controversies surrounding the development and funding of human embryonic stem cells have made some governments reluctant to support the research and even more disinclined to fund translational activities. This hesitancy has then discouraged other investors. CIRM, which has far more resources than other pluripotent stem cell funders, is an exception. It has made a major investment in funding clinical trials, but even CIRM will not be able to afford funding for many late-stage trials. One of the dilemmas in trying to assess funding patterns is that breakdowns by area of funding are not always available. Hence increases in funding for the pluripotent stem cell field do not necessarily carry over into the availability of resources for translation of the basic research. Translation of stem cell research has sometimes been characterized as the “valley of death.” One study of the challenges in the translation of cell therapies, focusing on the situation of companies developing adult stem cell products, reported that several interviewees identified acquiring sufficient funding to survive the therapy development process as the single biggest challenge facing firms in the field (Dodson and Levine 2015). Others have used the term “valley of death” specifically for the challenges of fundraising for the third stage of clinical trials. Because the third phase must recruit a far larger number of patients, it is significantly more expensive than the first two stages. As will be related in Chapter Five, Geron Corporation, one of the initial developers of pluripotent stem cell therapies, withdrew from the field midway through its first clinical trial, ostensibly for business reasons. Two of the stem cell companies whose clinical trials CIRM supported did not survive the third stage of trials, ostensibly due to business reasons and/or funding shortfalls (Chapman 2019).

U.S. Federal Funding The U.S. Federal government has played a key role in providing the funding for many innovative cutting-edge therapies and technologies. However, generous federal funding for the development of pluripotent stem cell therapies, particularly for human embryonic stem cell research and for supporting clinical trials, has not been forthcoming. Although President

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George W. Bush, much to the surprise of his supporters, decided to allow the federal government to fund human embryonic stem cell research, while confining authorization to lines already derived by August 2001, only a relatively small amount of money in the NIH budget was invested in this research during his administration. In Fiscal Year 2003, the NIH spent $517 million on stem cell research, but only $20 million of this was allocated for human embryonic stem cell research. At that time, work with human induced pluripotent stem cell research had not yet begun. The comparable figures for FY 2004 were $553 million for stem cell research but only $24 million for human embryonic research. When the total NIH budget was increased in FY 2005 $609 million went to stem cell research, of which $40 million went to human embryonic stem cell research. Table 4-1 details the NIH funding patterns for stem cell research between FY 2003 and FY 2007. Table 4-1: National Institutes of Health Funding for Stem Cell Research between FY 2003 and FY 2007 ($ in millions)

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FY03 Human embryonic 20 Non-human embryonic 113 Human non-embryonic 191 Non-human non-embryonic 192 Total stem cell research 517 Source: Johnson and Williams (2007), p. 13.

FY04 24 89 203 236 553

FY05 40 97 199 273 609

FY06 38 110 206 289 643

FY07 37 110 205 288 641

Many proponents of pluripotent stem cell research had hoped that President Barack Obama would substantially increase funding for human embryonic stem cell research. While President George W. Bush had political constraints on providing generous funding for human embryonic stem cell research, President Obama did not. Shortly after coming into office, President Obama did remove the policy constraints limiting the human embryonic stem cell lines eligible for federal funding that President Bush had imposed. During his administration, funding for the new category of induced pluripotent stem cells discovered in 2006 was initiated as well. In addition, the NIH allocated more funding to human embryonic stem cell research than had been the case under the Bush administration. However, human embryonic stem cell research continued to lag behind other categories of stem cell research. Moreover, when the NIH established its own intramural center to develop new therapies using stem cell approaches, it was originally named the NIH Center for Induced Pluripotent Stem Cells, presumably indicating it did not plan to support human embryonic stem cell research. It was later renamed the NIH Center for Regenerative Medicine in

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recognition of the therapeutic possibilities from applications of adult stem cells, but it became no more inclined to fund human embryonic stem cell research (Rao and Collins 2012). In FY 2009, the total amount of federal grants for embryonic and non-embryonic human stem cell research was augmented by money from the American Recovery and Reinvestment Act. Total federal funds for all categories of stem cell research amounted to $1231 million, of which $143 million went to human embryonic stem cell research, not quite 12 percent of the total. All forms of non-embryonic human stem cell research received $448 million. Funds going to non-embryonic non-human research were even greater: $638 million (Tarne 2018). During the Obama administration, there was a significant boost to the NIH budget. This made more money available for the stem cell field, including for human embryonic stem cell research. However, the NIH continued to fund other types of stem cell research more generously than human embryonic stem cell research. In FY 2016, near the end of the Obama presidency, $206 million in the $31 billion National Institutes of Health budget went to human embryonic stem cell research. In comparison, nearly twice as much, $374 million, was allocated for less controversial human induced pluripotent research. The $206 million in funding for human embryonic stem cell research constituted less than 14 per cent of the total funding for stem cell research (National Center for Health Statistics 2019, 5). Table 4-2 below presents the NIH funding patterns between FY 2013 and FY 2016. Table 4-2: National Institutes of Health Funding for Stem Cell Research between FY 2013 and FY 2016 ($ in Millions) FY13 FY14 FY15 FY16 Human embryonic stem cell research 146 166 180 206 Non-human embryonic stem cell research 154 150 159 146 Human induced pluripotent stem cell research 199 280 282 335 Non-human induced pluripotent stem cell research n.a. 49 56 374 Human adult stem cell research 466 505 524 727 Non-human adult stem cell research 613 627 632 652 Total Stem Cell Research 1273 1391 1516 1516 Sources: National Center for Health Statistics (2019). Figures are actuals, not estimates. This table does not reflect the additional category in the NIH table of induced pluripotent stem cells that are not designated as either human or nonhuman. The figures for human adult stem cell research for FY 2014–2016 include funding for umbilical cord blood/placenta.

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As of early 2020, the Trump administration had not yet defined a policy on funding embryonic stem cell research. However, key members of the administration, including Vice President Mike Pence and several cabinet members, believe human embryos should be protected and strongly oppose human embryonic stem cell research. Articles have appeared in conservative publications questioning why the administration is still investing $200 million per year in human embryonic stem cell research (Stonestreet and Morris 2019); but this has not, at the time of writing, led to a policy change. In 2017, a group of Republican conservatives in Congress lobbied the administration to remove Francis Collins from his position as Director of NIH, even though he is an evangelical Christian, because of his support for human embryonic stem cell research (Fox 2017). President Trump did not do. However, since the Trump administration did end federal funding for research using human fetal tissue, many stem cell scientists worry about continued support for stem cell research, particularly for human embryonic stem cell research.

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U.S. State Funding Programs The constraints on federal funding during the Bush administration and the uncertainty created by legal suits seeking to end federal funding for human embryonic stem cell research prompted several states to initiate programs to fund embryonic stem cell research. The programs sought to support researchers in their state and to enable them to use stem cell lines developed after 2001. Some states also assumed that it would be possible to recoup their investments through receiving royalties once therapies were marketed. The California Institute for Regenerative Medicine (CIRM) has been the most important of these state programs, dwarfing the investments made by the three next largest state programs, in Connecticut, New York, and Maryland. As noted, a 2004 referendum created CIRM with $3 billion in resources. Table 4-3 provides an overview of the resources anticipated to be available to the four major state stem cell research funding programs when they were established.

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Table 4-3: The Anticipated Resources for the Four Major State Stem Cell Research Funding Programs at the Time of Establishment

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California Connecticut First grant awarded 2006 2006 Initial funding/time $3B/10 $100M/10 period years years Approximate $300M $10M annual funding Source: Alberta et al. (2015), p. 116.

Maryland 2007 Funding from MD annual budget $14M

New York 2008 $600M/11 years $55M

The way the programs have allocated their funds has differed. CIRM has had sufficient resources to fund infrastructure for stem cell programs and to train scientists, to fund research at various stages, as well as to support translational activities. Much of CIRM’s funding in its early years, some $271 million, went to key universities in California to establish and develop infrastructure and research space for their stem cell research programs. The institutions receiving the CIRM funding were then able to leverage an additional $543 million in funds from private donors and institutions to construct and refurbish buildings. Beginning in 2009, CIRM began making major investments in research to California’s private and public universities and to private companies located in California (McCormack 2017). CIRM has provided research grants in various categories: inception, discovery-stage research, quest discovery projects that were farther along in their development, therapeutic translation projects to prepare for clinical trials, and clinical trials. By the middle of 2019, CIRM had funded 55 clinical trials, but not all of them were for stem cell research. Of those that were, only a few were testing pluripotent based therapeutics (California Institute for Regenerative Medicine, n.d.). In July 2019, CIRM announced that it was no longer accepting funding proposals for new projects (McCormack 2019). Its $3 billion in funding from the 2004 referendum was mostly expended at that point and the remainder would be used for existing commitments. CIRM will be seeking authorization from the voters in California in 2020 for $5.5 billion in new funding. Of the $600 million in NYSTEM’s overall budget commitment, $300 million was set aside to invest during the program’s first five years. This front-heavy budgeting focused mainly on funding basic research. The NYSTEM priorities were research at 65 to 80 percent; scientific training, 4 to 10 percent; infrastructure development at New York institutions, 10 to 15 percent (institutional development grants and large equipment grants); ethical, legal, and social issues and education, three to five percent (mostly

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educational programs); and administration, three to five percent (Empire State Stem Cell Board 2009). This front-loading meant that not very much of the funding was available for translational activities. Although NYSTEM continues to fund grants, the program is reluctant to disclose how much is being made available. The Connecticut stem cell funding program, initiated in 2006 with $100 million of tobacco settlement funds, spent down this money by 2015. Most of the grants made from the Connecticut program were to support early stage research. Like the other state funding programs, the largest grants were made to support the development of institutional stem cell cores at UConn (formerly the University of Connecticut) and Yale University, which would provide services and assistance to researchers at their respective universities. The state continued to provide funding for stem cell research from the state budget through 2018 but then ceased funding new grant recipients due to the state’s fiscal problems. The program is not officially closed as yet because grantees are still expending funds, but the stem cell core facilities were notified that they will not be getting any new funding after 2021. The Maryland stem cell funding program, which began with $14 million in funding from the state budget, was reduced to $10 million in 2018 and to $8.2 million in 2019 (Gincel 2019). The stated purpose of the Maryland Stem Cell Research Fund is to promote state-funded human stem cell research and medical treatments. To that end, it has several categories of funding: discovery grants for innovative groundbreaking ideas; validation grants for technologies that have intellectual property filed and commercial or clinical potential; commercialization grants for new start-up companies in Maryland or an existing company launching a new product; clinical grants for clinical trial sites in Maryland, and post-doctoral fellowships (Maryland Stem Cell Research Fund 2019).

UK Government Funding The Medical Research Council (MRC), one of seven UK research councils that receive funding from Parliament, is the lead government agency in the UK funding stem cell research. Additional support comes from three other UK councils: the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council, and the Economic and Social Research Council, along with UK research charities and the Department of Health. The MRC contributes approximately one-third of the UK research budget in this area. The MRC spent £44 million on stem cell research in the 2012/2013 financial year and in addition to the funds

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invested in basic stem cell biology, planned to commit £150 million to regenerative medicine between 2011 and 2015. In addition to supporting fundamental stem cell research and providing support for capacity building, the MRC has sought to further the translation of research into therapies (International Stem Cell Forum 2014). In 2012, the UK government made regenerative medicine one of its strategic priorities in science. The UK research councils established the UK Regenerative Medicines Platform (UKRMP), a £42 million initiative for its first four years, with a focus on targeting translational challenges in the regenerative therapy field. The first tranche of funding, £25 million (about $35 million) was used to support five interdisciplinary and complementary research hubs which drew together major players in UK regenerative medicine and to establish key research programs in several areas, and to train and support personnel on manufacturing processes. The second tranche of funding of £17 million (about $25 million) to support programs from 2018 until 2023 is to be invested in evolving and consolidating the structure of three hubs, one of which is pluripotent stem cell biology. The government decided to focus on scientific research and not to pursue clinical trials (UK Regenerative Medicine Platform, n.d.). To promote private sector development, Innovate UK, a public body, set up the Cell and Gene Catapult, a not-for-profit independent center intended to connect business with relevant research initiatives. Its central purpose is to build a world-leading cell and gene sector in the UK through helping cell and gene organizations translate early-stage research into commercially viable and investable therapies (Cell and Gene Therapy Catapult, n.d.).

Industry Funding Public sources of funding have had a more significant role in developing the pluripotent stem cell field than industry funding has. Several small biotechnology companies have played important roles, but the major pharma companies have been reluctant to invest significant resources. In assessing the investment of the small biotechnology companies, it is relevant to note that some of the funding these companies bring to stem cell research and translation comes from public sources, and the public funding can both provide critically needed resources and help to secure other sources of support. CIRM has provided loans and grants to many of the stem cell companies operating in California. Not all of these companies, however, are focusing on pluripotent stem cells or even stem cell therapies, and not all of this funding is for translational purposes, but some of it is. CIRM, for

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example, has played a critical role in providing funding for clinical trials conducted by several small biotechnology companies. As of mid-2019, CIRM had made grants or loans to 16 such companies to conduct stem cell clinical trials, and six of these companies received CIRM support to conduct two clinical trials (California Institute for Regenerative Medicine, n.d.). The Maryland Stem Cell Research Fund also supports corporations conducting stem cell research in its state. Three pioneering small biotechnology corporations played a significant role in the early development of the pluripotent stem cell field. Geron Corporation, a California-based company, developed a therapy containing oligodendrocyte progenitor cells derived from human embryonic stem cells for patients with spinal cord injuries. CIRM made a $25 million grant to Geron Corporation to support its first-in-human pluripotent stem cell trial of this cell therapy (Kaiser 2011). Geron began the clinical trial in 2010, but when a change in corporate leadership occurred the next year, it discontinued the trial and decided to withdraw from the field. In 2012, BioTime’s Asterias subsidiary, headed by the former Geron CEO, acquired Geron’s human embryonic stem cell assets (Akst 2012). Asterias has subsequently received FDA approval to continue Geron’s clinical trial and, like Geron, received funding from CIRM. More about this clinical trial and other pluripotent stem cell clinical trials will be discussed in Chapter Six. Advanced Cell Technology, a Massachusetts-based company that changed its name to Ocata Therapeutics, Inc. and then was acquired by Astellas Pharma, developed the single-cell blastomere process to derive human embryonic stem cell lines without destroying an embryo, as mentioned in Chapter Two. Its human embryonic stem cell therapies have focused on retinal diseases. It has developed therapies for macular degeneration and Stargardt’s disease and conducted Phase I and Phase II clinical trials to test them. ViaCyte, a California-based company, is seeking to advance cures for insulin dependent diabetics with a human embryonic stem cell–based therapy that is implanted in the body, housed in a tiny capsule. The use of the implanted device is to grow cells and dispense insulin as needed to regulate glucose levels. Viacyte has also conducted Phase I clinical trials. Notably, ViaCyte has received more money, $72 million, from CIRM than any other enterprise (Jensen 2018).

Cell Processing and Manufacture Current regulatory standards attempt to ensure investigational products have been proven to be safe, effective, and of high quality before their

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clinical application is approved. Stem cells present greater problems for quality control in their processing and manufacture than small molecule– based medical products. Biologics in general and pluripotent stem cells in particular have characteristics that complicate assurances of quality, safety, and efficacy. Cells in culture age and, as they do, may accumulate genetic and epigenetic changes that affect their differentiation behavior and function. Pluripotent stem cells have additional risks because pluripotency makes them prone to acquire mutations when maintained in culture for prolonged periods, to differentiate into inappropriate cellular phenotypes, to form benign teratomas and sometimes malignant outgrowths as well, and to fail to mature. Scientific understanding of how to control these processes is still evolving (International Society for Stem Cell Research 2016, sec. 3.1.2). Compared with pharmaceuticals, biologics, and somatic cellular therapies, pluripotent stem cell–based products have a distinctive dynamic heterogeneity that increases uncertainty and safety risks. Cells are in a constant state of flux (Hyun 2013, 54). Moreover, even minimal manipulation of cells outside the human body introduces additional risks of contamination with pathogens. Also, as cells in culture age they are prone to accumulate genomic and epigenomic mutations that could lead to altered cell function or malignancy. Therefore, cell-based products need to be rigorously assessed at all stages of manufacture. The manufacturing side presents additional challenges related to quality control, scalability, sustainability, and the costs of the goods. Cellbased therapies require that cells be produced in sufficient numbers with reproducible quality and at relatively low cost either before or during the clinical assessment phase. To do so requires suitable manufacturing technology to expand the cells without negatively affecting their characteristics and therapeutic potential. The dilemma is that the therapeutic potential of cells is known to deteriorate with time in culture. Moreover, the manufacture of products intended for human use must be done under good manufacturing practices (GMP) (Heathman et al. 2015). Development of technologies to achieve large-scale cell manufacturing is still at an early stage. (International Society for Stem Cell Research 2016, sec. 3.1.2). Differing standards for NIH determination of stem cell eligibility for federal funding, as indicated by listings in the NIH Stem Cell Registry, and FDA requirements for human applications, render most established pluripotent cell lines inappropriate for the development and marketing of therapeutic products. The FDA requires that the potential donor of human tissue and the embryos from which human embryonic stem cell lines are developed must be tested and demonstrated to be negative for or nonreactive to a wide range of infectious agents and diseases in order for the candidate

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product to be eligible for therapeutic use. For basic pluripotent stem cell research, it does not matter that the source of the embryo or tissue has not been screened. However, the absence of embryo donor testing, as is the case for the overwhelming majority of the lines on the NIH Stem Cell Registry, perhaps even all of them, likely excludes them from serving as the basis for therapies going into clinical trials (Jonlin 2014). This is not only a setback for researchers who have focused on particular lines for their research. It also raises yet again the ethical and religious issues related to the development of new embryonic stem cell lines. Nor does there seem to be an easy solution for this problem. The FDA Tissue Donor Guidance governing biologically generated products does not recognize the testing of already existing pluripotent stem cell lines as an option. Nor in most cases is it feasible to screen IVF patients at the time they initiate treatment, due to the extra cost and the question of who would pay for it. Similarly, testing and interviewing couples at the time of embryo donation might be considered an invasion of privacy as well as again raise the issue of who would assume responsibility for the extra cost. Moreover, by imposing a substantial hurdle for donation of surplus embryos, it would likely discourage many couples from doing so (Jonlin 2014). Adhering to GMP quality standards is another requirement to meet FDA and European Medicines Agency (EMA) standards for clinical-grade cells. GMP is a quality assurance system used in the pharmaceutical field to assure that the end product meets preset standards that cover both manufacturing and testing of the final product. Deriving, bioprocessing, and manufacturing human pluripotent stem cells according to GMP standards presents multiple technological challenges and significantly increases the time and expense for translation (Abbasalizadeh and Baharvand 2013). Moreover, GMP standards for stem cell–based therapies are yet to be universally agreed upon (Hyun 2013, 55). Meeting GMP standards minimally necessitates deriving, culturing, expanding, and preserving cells using animal substance–free media, feeder cells, and matrix. It is only recently that these xeno-free conditions have become available. The goal is to protect against infectious risk and immune reactions to animal proteins in the cells. Very few of the thousands of existing pluripotent stem cell lines can meet these standards. The safest and most feasible option to obtain clinical-grade cells would be to derive the lines from their beginning stages according to GMP standards (Unger et al. 2008). This is what several groups have done (Crook et al. 2007; Gu et al. 2017).

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Additionally, it is necessary to modify the manufacturing process as research proceeds from a Phase I clinical trial with only a few patients to Phase II and III trials with significantly more patients and much larger supply demands. Moreover, a clinical trial sponsor must be able to convince regulators that the product is the same with regard to its identity, purity, viability, and potency during the scaling up of the process. This can be both very expensive and time-consuming. Scaling up cell production is not equivalent to replicating a small-scale process a multiple number of times. It often requires new systems for culturing, expanding, and manipulating cells. For cell manufacturers to expand or transfer lines from one facility to another or among several facilities could also entail developing new ways of storing, packaging, or transporting cells (Baum et al. 2013).

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The Promotion of Unapproved Stem Cell Applications and Its Implications For all of the reasons discussed in this chapter, translation of pluripotent stem cell research into therapies is a slow and challenging process. However, many patients and patient advocate groups, encouraged by overly optimistic stakeholder claims seeking funding and support coupled with intense media coverage of the field, have unrealistic expectations of the near-term availability of stem cell cures. In such a situation, many patients are likely to be disappointed and frustrated by the slow progress of the science. Desperate for cures, patients with serious medical problems may seek available alternatives, even if the options entail treatment with untested and/or unapproved stem cell treatments despite when doing so is likely to be problematic. Use of experimental stem cell treatments early in the clinical trial process before regulatory approval or outside of controlled clinical trials exposes patients to considerable risk. It may also jeopardize the integrity of and public trust in stem cell medical research (Daley 2012, 747). Some stem cell researchers worry that patients who have heard about problems resulting from unapproved stem cell therapies may be reluctant to participate in legitimate stem cell trials, making it difficult to recruit sufficient numbers of candidates (Boodman 2019). While the desire of patients, particularly those with terminal illnesses or medical problems who have few treatment options, to seek access to experimental therapies is not a new issue, the recent passage of right-to-try laws by more than 40 states, followed by the adoption of a federal right-to-try law in 2018, has complicated matters. In contrast with the older FDA compassionate access program for patients with lifethreatening diseases or serious illnesses who are ineligible for or unable to

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participate in clinical trials, these right-to-try laws do not require FDA review or IRB approval, which had provided protections under the FDA program. The 2018 federal right-to-try law also has broader eligibility criteria than the FDA compassionate access program. It applies to patients with chronic, but not immediately life-threatening, conditions. While the FDA was more likely to grant access to investigational drugs that had gone through at least two stages of clinical trials, the right-to-try laws require only the completion of one stage. It is relevant to note that Phase I trials typically involve very small numbers of participants and are designed to evaluate safety and dosage levels, not effectiveness. Moreover, less than 20 percent of drugs that satisfactorily complete Phase I safety testing eventually attain market approval (Resnik 2018). Therefore, the therapies accessed through the right-to-try track pose considerable risk to patients – particularly investigational pluripotent stem cell–based therapeutics, since these are often first-in-human trials. Despite the name, the right-to-try laws do not provide patients with a right of access to investigational therapies. Access depends on the willingness of the pharmaceutical manufacturer to make the investigational therapy available. It does not require them to do so, and the majority may be disinclined or not have sufficient product available to provide investigational therapies upon request. As of early 2019, four stem cell companies had announced that they will make stem cell products available under right-to-try laws: Therapeutic Solutions International, BrainStormCell Therapeutics, Creative Medical Technologies, and Pluristem Therapeutics, all of which make therapeutics based on adult stem cells (Folkers, Chapman, and Redman 2019). More problematically, untested and unapproved stem cell therapies are being promoted and marketed for a variety of medical problems. Playing on the hype about stem cell treatments, unlicensed clinics have opened in the United States and other countries that are purveyors of unapproved treatments for which no clear evidence of effectiveness exists. These usually come at a very considerable cost to patients, who are charged from thousands to tens of thousands of dollars (Turner 2015). California, the center of stem cell research and translation, also leads the country in the number of unregulated stem cell clinics. Recent estimates are that California has more than 100 such clinics, more than any other state in the U.S. (Jensen 2019), suggesting there is a correlation between publicity and hype about the stem cell field and the vulnerability of patients to the wares of dubious clinics. Because these clinics do not make public their clinical protocols or publish peer-reviewed data, little is known about what kinds of stem cells are being administered to patients. Many researchers even question whether patients are receiving actual stem cells (Turner 2015).

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Patients who look to stem cell therapies as a means to alleviate their suffering or cure their loved ones often cannot differentiate between tested and authorized treatments and untested or unauthorized ones. In the information age, all it takes is an online search to find myriad websites promoting stem cell treatments, often with compelling patient testimonials. Some patients also assume that if a therapy is listed on the clinicaltrials.gov website then it is authentic, but this NIH database does not review its listings to certify them. It is more like the Wikipedia of clinical trials: open to anyone putting up a posting, with the authenticity of the post dependent on the reliability of the poster (Boodman 2019). A marketing ploy of some clinics is to claim that they are conducting pay-to-participate clinical studies, which they then seek to register on the database clinicaltrials.gov to provide an aura of legitimacy for what they are doing. Unauthorized studies initiated by stem cell companies charging $7500 to $20,000 per patient have been registered in the database in recent years (Rubin 2018). This is not solely a U.S. problem. Clinics offering unauthorized stem cell therapies for a wide range of diseases and conditions have been established throughout the world, both in countries with weak regulatory systems, including a large number in China and India, and in those with stronger regulatory systems, as in Europe. Stem cell clinics market their treatments as “natural” alternatives to major surgery that harness the body’s innate ability to grow and heal itself. Various clinics claim they can treat neurological, autoimmune, orthopedic and degenerative diseases, including Parkinson’s, amytotrophic lateral sclerosis (A.L.S.), lung disease, heart disease, back trouble, arthritis, and other problems (Grady 2019). Relief from orthopedic problems and pain are the most common claims made by the clinics (Rubin 2018). One search conducted in 2016 found 351 U.S. businesses engaged in direct-to-consumer marketing of unapproved stem cell interventions offered at 570 clinics (Turner and Knoepfler 2016). By 2018, estimates were that there might be 700 to 750 such clinics in the U.S. (Rubin 2018) and likely thousands more globally. Autologous cell therapies are promoted as being risk free, but such treatments have been shown to have potential risks to health, some quite serious. Moreover, the results of a recent survey indicate that bad outcomes are much more common than was realized. One in four had patients with complications related to unauthorized stem cell therapy (Julian, Yuhasz, Rai, Salerno et al. 2020). Complications have included blindness, meningitis, brain tumors, spinal cord tumors, lesions of the spinal cord and even death (Berkowitz et al. 2016; McGinley and Wan 2018; Institute of Medicine and National Academy of Sciences 2014, 15). In one recent incident, a dozen patients required hospitalization after receiving injections

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supposedly containing stem cells from umbilical cord blood that led to infections in the bloodstream or joints (Grady 2018). Sometimes the problems from the stem cell treatments, such as tumor formation, arise as much as 12 years later (Flaherty 2019). Some U.S. clinics argue they are not subject to FDA regulations because they administer patients’ own cells, claiming they are not making new drugs. Another of their arguments is that they are engaged in the practice of medicine, which the FDA does not directly regulate (Turner 2015, 567). However, the FDA insists these therapies require advance approval because the cells are intended to treat diseases, undergo substantial processing, and are being used in ways that are different from their original purposes. The disputes between the FDA and the clinics led to a defining case in which the DC Circuit Court of Appeals ruled in 2014 that an intervention that involves culturing and expanding a patient’s autologous stem cells before reimplantation was subject to FDA regulation because the procedure involved more than “minimal manipulation” (Matthews and Iltis 2015). In another case, in 2019, a federal judge granted the FDA’s motion for summary judgment against U.S. Stem Cell, holding that the defendants had adulterated and misbranded a stem cell drug product made from a patient’s adipose tissue. Three patients treated by the clinic had gone blind from injections into their eyes. These decisions confirmed that the FDA has the authority to regulate the stem cell industry (Grady 2019), but whether the FDA will do so is questionable. While the FDA has oversight over human stem cell therapies, it has taken an industry-friendly approach and only recently took some initial steps to regulate rogue clinics. Between 2010 and 2017, the agency sent warning letters to only seven of the hundreds of companies that marketed stem cell treatments (Chen 2019). The agency has now issued warning letters to several other clinics and ordered a few to close down. It also announced that enforcement will tighten in 2020 (Grady 2018), but it has yet to occur. Former FDA Commissioner Scott Gottlieb has acknowledged that the agency’s laissez-faire attitude has made it easier for these rogue stem cell clinics to proliferate. According to Gottlieb, “This is an example where the F.D.A., for a long period of time, took enforcement discretion, then the field grew…Then it becomes hard to step in and actually apply the regulation” (Chen 2019). In view of the difficulty of curbing the entire industry, FDA officials plan to focus initially on high-risk procedures such as injections into the brain, spinal cord, and eye (McGinley and Wan 2018). Frustration with the FDA’s inaction has led a few states to begin to take action. The Medical Board of California Task Force has announced that it will investigate stem cell clinics in the state (Knoepfler 2018), but

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whether this will lead to meaningful action is another question. Proposed legislation to regulate “snake oil” stem cell clinics in California hit a fiscal speed bump after a cost of $100,000 was assigned to the measure (Jensen 2019). Letitia James, the Attorney General of New York, has filed a lawsuit charging one for-profit clinic with performing unproven, rogue procedures on patients. In a statement she said that “Misleading vulnerable consumers who are desperate to find a treatment for medical conditions is unacceptable, unlawful, and immoral” and vowed to continue to investigate the clinics that add to the suffering of patients by charging them thousands of dollars for treatments they know are ineffective (Abelson 2019).

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Reflections Researchers and product developers who are trying to bring pluripotent stem cell therapies to the clinic face significant translational challenges that involve a long, complex, and costly process. However, the public does not understand these hurdles. This discrepancy between the complexity of the translational process and the expectations of the public, particularly patients and their advocates, is problematic. It has led to frustrations and disappointment, and encouraged the development of hundreds, perhaps thousands, of fraudulent stem cell clinics that can both harm patients and undermine confidence in stem cell science. Even more worrisome, because the translation of pluripotent stem cells into therapies will depend on continuing and increased public funding, the lack of understanding about the complexity of the translational process and the resulting long timelines for the development of therapies risks the loss of this necessary public financial support. Hopefully, it will not undermine CIRM’s effort to seek a second trough of funding through a second referendum in 2020.

References Abbasalizadeh, Saeed, and Hossein Baharvand (2013) “Technological Progress and Challenges Towards cGMP Manufacturing of Human Pluripotent Stem Cells Based Therapeutic Products for Allogeneic and Autologous Cell Therapies.” Biotechnology Advances 31 (8): 1600– 1623. Abelson, Reed (2019) “State Sues Manhattan Stem Cell Clinic.” The New York Times, April, A21. Akst, Jef (2012) “Geron’s Stem Cell Program Sold.” The Scientist, October. https://www.the-scientist.com/the-nutshell/gerons-stem-cell-programsold-38604.

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Alberta, Hillary B., Albert Cheng, Emily L. Jackson, Matthew Pjecha, and Aaron D. Levine (2015) “Assessing State Stem Cell Programs in the United States: How Has State Funding Affected Publication Trends?” Cell Stem Cell 16 (2): 115–18. Baum, Elona, Neil Littman, Morrie Ruffin, Stephen Ward, and Kathy Aschheim (2013) “Key Tools and Technology Hurdles in Advancing Stem-Cell Therapies.” California Institute for Regenerative Medicine; Alliance for Regenerative Medicine Cell Therapy Catapult. Berkowitz, Aaron L., Michael B. Miller, Saad A. Mir, Daniel Cagney, Vamsidhar Chavakula, Indira Guleria, Ayal Aizer, Keith L. Ligon, and John H. Chi (2016) “Glioproliferative Lesion of the Spinal Cord as a Complication of ‘Stem-Cell Tourism’.” New England Journal of Medicine 375 (2): 196–98. Boodman, Eric (2019) “Stem Cell Clinics Co-Opt Clinical-Trials Registry to Market Unproven Therapies, Critics Say.” STAT, June. https://www.statnews.com/2019/06/11/stem-cell-clinics-clinical-trialsdot-gov/. California Institute for Regenerative Medicine (n.d.) “Beyond Cirm 2.0: Proposed Strategic Plan: 2016 & Beyond” (Accessed 23 May 2020). https://www.cirm.ca.gov/sites/default/files/files/agenda/151217_Agend a_7_CIRM_StratPlan_final_120815.pdf. California Institute for Regenerative Medicine (n.d.) “Funding Clinical Trials” (Accessed 23 May 2020). https://www.cirm.ca.gov/clinicaltrials. Cell and Gene Therapy Catapult (n.d.) “Cell and Gene Therapy Catapult” (Accessed 23 May 2020). https://ct.catapult.org.uk/. Chapman, Audrey R. (2019) “What Can We Learn from California Institute for Regenerative Medicine’s First 50 Clinical Trials?” Regenerative Medicine 14 (10): 899–903. Chen, Caroline (2019) “The Birth-Tissue Profiteers.” The New Yorker, May. https://www.newyorker.com/news/news-desk/the-birth-tissueprofiteers. Crook, Jeremy Micah, Teija Tuulikki Peura, Lucy Kravets, Alexis Gina Bosman, Jeremy James Buzzard, Rachel Horne, Hannes Hentze, et al. (2007) “The Generation of Six Clinical-Grade Human Embryonic Stem Cell Lines.” Cell Stem Cell 1 (5): 490–94. Daley, George Q. (2012) “The Promise and Perils of Stem Cell Therapeutics.” Cell Stem Cell 10 (6): 740–49. Dodson, Brittany P., and Aaron D. Levine (2015) “Challenges in the Translation and Commercialization of Cell Therapies.” BMC Biotechnology 15 (1): 70.

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Empire State Stem Cell Board (2009) “2008-09 Annual Report.” New York State Department of Health (Chair: Richard F. Daines). Flaherty, Brittany (2019) “Canada Case Highlights Possible Long-Term Risks of Experimental Stem Cell Therapy.” STAT, July. https://www.statnews.com/2019/07/11/canada-case-long-term-risksexperimental-stem-cell-therapy/. Folkers, Kelly, Carolyn Chapman, and Barbara Redman (2019) “Federal Right to Try: Where Is It Going?” Hastings Center Report 49 (2): 26– 36. Fox, Maggie (2017) “Conservative Reps Urge Trump to Fire Nih Chief Francis Collins over Stem Cells.” NBC News, May. https://www.nbcnews.com/health/health-news/conservative-reps-urgetrump-fire-nih-chief-francis-collins-over-n763301. Gincel, Dan (2019). Email to the author. Grady, Denise (2018) “A Dozen Patients Require Hospitalization After Receiving Stem Cell Injections.” The New York Times, December, A13. Grady, Denise (2019) “F.D.A. Can Act Against Stem Cell Clinic, Judge Rules.” The New York Times, June. https://www.nytimes.com/2019/06/03/health/stem-cell-fdaregulate.html. Gu, Qi, Juan Wang, Lei Wang, Zheng-Xin Liu, Wan-Wan Zhu, Yuan-Qing Tan, Wei-Fang Han, et al. (2017) “Accreditation of Biosafe ClinicalGrade Human Embryonic Stem Cells According to Chinese Regulations.” Stem Cell Reports 9 (1): 366–80. Heathman, Thomas R. J., Alvin W. Nienow, Mark J. McCall, Karen Coopman, Bo Kara, and Christopher J. Hewitt (2015) “The Translation of Cell-Based Therapies: Clinical Landscape and Manufacturing Challenges.” Regenerative Medicine 10 (1): 49–64. Hyun, Insoo (2013) Bioethics and the Future of Stem Cell Research. Bioethics and the Future of Stem Cell Research. New York: Cambridge University Press. Institute of Medicine and National Academy of Sciences (2014) Stem Cell Therapies: Opportunities for Ensuring the Quality and Safety of Clinical Offerings: Summary of a Joint Workshop. Washington, DC: The National Academies Press (Rapporteurs: Adam C. Berger, Sarah H. Beachy, and Steve Olson). International Society for Stem Cell Research (2016) Guidelines for Stem Cell Science and Clinical Translation. http://www.isscr.org/guidelines2016.

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International Stem Cell Forum (2014) “Medical Research Council (Uk).” International Stem Cell Forum (Internet Archive, captured November 7, 2019). http://www.stem-cell-forum.net/medical-research-council-uk-3/. Jensen, David (2018) “The Valley of Death and the California Stem Cell Agency: Luring Deep Pocket Investors.” California Stem Cell Report Blog, November. http://californiastemcellreport.blogspot.com/2018/11/the-valley-ofdeath-and-california-stem.html. Jensen, David (2019) “Legislation to Regulate ’Snake Oil’ Stem Cell Clinics in California Hits Fiscal Speed Bump.” California Stem Cell Report Blog, May. http://californiastemcellreport.blogspot.com/2019/05/legislation-toregulate-snake-oil-stem.html. Johnson, Judith A., and Erin D. Williams (2007) “Stem Cell Research: Federal Research Funding and Oversight.” Congressional Research Service Reports 39 (Updated April 18, 2007). Jonlin, Erica C. (2014) “Differing Standards for the NIH Stem Cell Registry and FDA Approval Render Most Federally Funded hESC Lines Unsuitable for Clinical Use.” Cell Stem Cell 14 (February): 139–40. Julian, Katherine, Nicholas Yuhasz, Widjan Rai, Jose Salerno, Jaime Imtola (2020) “Complications from ‘Stem Cell Tourism,’” Annals of Neurology, https:// doi.org/10.1002/ana.25842. Kaiser, Jocelyn (2011) “CIRM Awards $25 Million for Geron’s Embryonic Stem Cell Trial.” Science, May. https://www.sciencemag.org/news/2011/05/cirm-awards-25-milliongerons-embryonic-stem-cell-trial. Knoepfler, Paul (2018) “Medical Board of California Task Force to Investigate Stem Cell Clinics.” The Niche: Knoepfler Lab Stem Cell Blog, November. https://ipscell.com/2018/11/medical-board-ofcalifornia-task-force-to-investigate-stem-cell-clinics/. Maryland Stem Cell Research Fund (2019) “Funding Opportunities.” Maryland Stem Cell Research Fund (Accessed 23 May 2020). https://www.mscrf.org/funding-opportunities/. Mathews, Kirstin R. W., and Ana S. Iltis (2015) “Unproven Stem Cell– Based Interventions and Achieving a Compromise Policy Among the Multiple Stakeholders.” BMC Medical Ethics 16 (1): 75. McCormack, Kevin (2017) “Building California’s Stem Cell Research Community, from the Ground up.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, October. https://blog.cirm.ca.gov/2017/10/16/building-californias-stem-cellresearch-community-from-the-ground-up/.

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McCormack, Kevin (2019) “Breaking Bad News to Stem Cell Researchers.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, July. https://blog.cirm.ca.gov/2019/07/01/breakingbad-news-to-stem-cell-researchers/. McGinley, Laurie, and William Wan (2018) “Miracle Cures or Modern Quackery? Stem Cell Clinics Multiply, with Heartbreaking Results for Some Patients.” The Washington Post, April. https://www.washingtonpost.com/national/health-science/miraclecures-or-modern-quackery-stem-cell-clinics-multiply-withheartbreaking-results-for-some-patients/2018/04/29/80cbcee8-26e111e8-874b-d517e912f125_story.html. National Center for Health Statistics (2019) “Estimates of Funding for Various Research, Conditions, and Disease Categories.” https://report.nih.gov/categorical_spending.aspx. Rao, Mahendra S., and Francis S. Collins (2012) “Steering a New Course for Stem Cell Research: NIH’s Intramural Center for Regenerative Medicine.” Stem Cells Translational Medicine 1 (1): 15–17. Resnik, David B. (2018) “Difficulties with Applying a Strong Social Value Requirement to Clinical Research.” Hastings Center Report 48 (6): 35– 37. Rosemann, Achim (2014) “Why Regenerative Stem Cell Medicine Progresses Slower Than Expected.” Journal of Cellular Biochemistry 115 (12): 2073–6. Rubin, Rita (2018) “Unproven but Profitable: The Boom in US Stem Cell Clinics.” JAMA 320 (14): 1421–3. Stonestreet, John, and G. Shane Morris (2019) “President Trump, Why Are We Still Funding Embryonic Stem Cell Research?” The Christian Post, December. https://www.christianpost.com/voice/president-trump-whyare-we-still-funding-embryonic-stem-cell-research.html. Tarne, Eugene C. (2018) “Trends Show More Federal Funds Awarded to Non-Embryonic Stem Cell Research.” Charlotte Lozier Institute (Accessed 23 May 2020). https://lozierinstitute.org/trends-show-morefederal-funds-awarded-to-non-embryonic-stem-cell-research/. Trounson, Alan, Elona Baum, Don Gibbons, and Patricia Tekamp-Olson (2010) “Developing a Case Study Model for Successful Translation of Stem Cell Therapies.” Cell Stem Cell 6 (6): 513–16. Turner, Leigh G. (2015) “Federal Regulatory Oversight of US Clinics Marketing Adipose-Derived Autologous Stem Cell Interventions: Insights from 3 New FDA Draft Guidance Documents.” Mayo Clinic Proceedings 90 (5): 567–71.

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Turner, Leigh, and Paul Knoepfler (2016) “Selling Stem Cells in the Usa: Assessing the Direct-to-Consumer Industry.” Cell Stem Cell 19 (2): 154–57. UK Regenerative Medicine Platform (n.d.) “Our Background.” UK Regenerative Medicine Platform (Accessed 23 May 2020). https://www.ukrmp.org.uk/about-us/background/. Unger, Christian, Heli Skottman, Pontus Blomberg, M. Sirac Dilber, and Outi Hovatta (2008) “Good Manufacturing Practice and Clinical-Grade Human Embryonic Stem Cell Lines.” Human Molecular Genetics 17 (R1): R48–R53.

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CHAPTER FIVE

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THE CALIFORNIA INSTITUTE OF REGENERATIVE MEDICINE (CIRM)

The derivation of human embryonic stem cells in 1998 engendered what might be termed an outbreak of extravagant hope from many patients and their families that scientists had discovered a new path to the development of therapies for hitherto incurable devastating human diseases. This hope turned to disappointment when President Bush refused to allow federal funding for research involving the use of any human embryonic stem cell lines created after August 2001 and only invested limited federal funding in human embryonic stem cell research. Moreover, to conform to federal policies, institutions that received nonfederal funding for human embryonic stem cell research could not use equipment or buildings that had been purchased or constructed with federal funds to conduct research with it. Additionally, threatened legal action from groups opposed to any form of federal funding for human embryonic stem cell research jeopardized the continuation of any federal funding for research involving human embryonic stem cells. Since this was several years before researchers discovered how to reprogram somatic cells into a pluripotent state, no alternative sources of pluripotent human cells were available. In response to these limits, a group of Californians led by Robert Klein, Jr., a Silicon Valley real estate developer who had a son with Type 1 diabetes, mounted a campaign to make generous funding available for human embryonic stem cell research in their state. Their proposal was to raise $3 billion through a public initiative in order to create a comprehensive state stem cell research program. To do so, they drafted a ballot proposition for the next election that would issue $3 billion in state bonds to fund embryonic stem cell research and mounted a campaign to convince voters of its potential benefits. Their initiative, known as the California Research and Cures Initiative, appeared on the ballot as Proposition 71. The campaign claimed that adopting this initiative would enable the development of new, life-changing therapies and implied that these therapies would become available in just a few years. The proponents also said that Proposition 71

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would create thousands of jobs and potentially return the state’s investment many times over. The Republican governor, Arnold Schwarzenegger, and more than 20 Nobel Prize laureates backed the initiative, as did Hollywood celebrities Michael J. Fox and Brad Pitt. Radio and television ads featured appeals from people with incurable diseases and injuries such as “Superman” actor Christopher Reeve, paralyzed from the neck down after a horseback riding accident. The initiative engendered heated debate, with the Catholic Church and other antiabortion groups opposing it on religious and ethical grounds. In November 2004, Proposition 71 – to fund, facilitate, and provide oversight for stem cell research in the state – was put to the voters in the general election. The initiative was successful: it was supported by 59 percent of the voters (Allday and Palomino 2018; Adelson and Weinberg 2010). Fifteen years later, as the funds authorized through Proposition 71 are nearly spent, some of those involved in the campaign concede that proponents overpromised its clinical and economic returns. They now acknowledge that developing cures within a relatively short period of time was not likely, but they also proudly point out “We have developed a regenerative medicine juggernaut” (Allday and Palomino 2018). And that they did. Proposition 71 authorized the sale of general obligation bonds to raise $3 billion for stem cell research over ten years, subject to an annual limit of $295 million, with interest payable from the state’s general fund. Using bonds to finance scientific research is unusual. This funding mechanism meant that future generations would bear the burden of repayment, as they do with other bond measures used to finance public works projects, though it could be argued that future generations would also share in the benefits of the knowledge and therapies obtained through this funding. According to the text of Proposition 71, the bonds were to be used to support stem cell research and research facilities, emphasizing pluripotent stem cell and progenitor cell research. The major direction given was to “Maximize the use of research funds by giving priority to stem cell research that has the greatest potential for therapies and cures, specifically focused on pluripotent stem cell and progenitor cell research among other vital research opportunities” (Institute of Medicine 2013, Appendix C: Proposition 71). However, as the chapter will indicate, CIRM has not focused exclusively, or at times even primarily, on pluripotent stem cell research. Proposition 71 has been characterized as “a bold social innovation” (Institute of Medicine 2013, 4) and “a major departure, perhaps even a paradigm shift, in how a publicly funded medical research program can be organized” (Acosta and Golub 2016, 423). It did mark a new phase in

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biomedical research in which a state, rather than the federal government, financed a major undertaking in an emerging and – at that time – unproven area. “Biomedically, this was California’s version of the Manhattan Project” (Burgin 2010, 78). The implementation of the initiative was initially delayed by lawsuits in state court by those opposed to Proposition 71. The litigation also delayed for three years the sale of bonds for funding. Ultimately, the legal suits were resolved and the California Institute for Regenerative Medicine (CIRM), the implementing and oversight agency for Proposition 71, was given a secure legal foundation (Adelson and Weinberg 2010, 448). Robert Klein, the sponsor of the initiative, became the first chairman of the agency. This chapter provides an overview of CIRM’s role in developing the pluripotent stem cell field. It offers an overview of its programs and investments, their strengths and limitations, and CIRM’s accomplishments. It is particularly appropriate to take stock now: at the time of writing (February 2020), after stretching the original 10 years of funding into 15 years of grant making, CIRM has spent most of the $3 billion made available through Proposition 71. In June 2019, CIRM announced that it was no longer accepting new grant applications and would use its remaining funds for existing commitments. CIRM’s advocates are preparing to turn to the voters in 2020 for another bond initiative, this time in the amount of $5.5 billion, to continue its program. Robert Klein is again heading the initiative.

CIRM’s Organization Proposition 71 contains both constitutional and statutory provisions that, among other things, enshrined the right to conduct human embryonic stem cell research in the California state constitution and created the California Institute of Regenerative Medicine (CIRM). CIRM’s mandate was to implement a funding initiative through making grants and loans for stem cell science and issuing bonds to pay for its operations and these grants and loans. CIRM is a semiautonomous institution not subject to legislative oversight and regulatory restrictions. The governor also has no official oversight role. Like many organizations, CIRM has a divided executive leadership with both a President and a Chairman. The President serves as the institution’s Chief Executive Officer, and the Chairman has significant management responsibility for operations and for the management of the Independent Citizens Oversight Committee. The Little Hoover Commission, an independent California state agency that investigates state government

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operations in order to promote efficiency and improved service, called for CIRM and the legislature to eliminate the overlapping authority between the President and the Chairman and to improve the accountability of both. CIRM has not adopted any of the commission’s recommendations as to how to do so. Although CIRM operates as an agency of the state executive branch, its governing board, the 29-member Independent Citizens Oversight Committee (ICOC) established by Proposition 71, has sole responsibility for CIRM’s governance and administration. The ICOC also administers CIRM’s financing along with the California Stem Cell Research and Cures Finance Committee, a state agency created by the Proposition 71 to handle the bond issues. The ICOC is unusual in that a majority of its members come from groups with a direct interest in the grants and loans CIRM makes. Proposition 71 specified this composition of advocates for different sectors rather than independent experts, presumably to build support for CIRM and encourage CIRM to be responsive to the presumed needs of constituents. The governing board is composed of university researchers and administrators, patient advocates, and representatives of the biotechnology industry, all from California. Particularly unusual is that ten members of CIRM’s 29member board are what CIRM calls patient advocates. These patient advocates participate in the review of grant applications and vote on final funding decisions on the same basis as other board members. As described by CIRM, the ICOC is composed of Californians with expertise in: “(1) managing large research grants and complex institutions and conducting cutting edge medical research; (2) understanding the critical path for the development of successful experimental medical treatments and directing the approval process through the Food and Drug Administration and other regulatory bodies and ethical committees; and (3) advocating on behalf of Californians who suffer from a variety of chronic diseases and injuries” (California Institute for Regenerative Medicine, n.d.). The large size of the ICOC, and its dual role making decisions usually handled by staff, such as grant selection, while also providing oversight, have been criticized. The Institute of Medicine (IOM) of the National Academy of Sciences (NAS) Committee, which conducted a review of CIRM in 2012 – at the request of and financed by CIRM – while generally positive in its assessment, recommended that CIRM should separate operations from oversight. It proposed that the board should focus on strategic planning, oversee financial performance and legal compliance, and assess the performance of senior management, but that it not be involved in day-to-day management (Institute of Medicine 2013, 6). CIRM did not adopt this recommendation.

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The composition of the ICOC has met with criticisms at several points in CIRM’s history because of the perceived conflicts of interest of its members. The IOM committee reviewing CIRM acknowledged that the board members’ personal and professional interests in the activities of CIRM brought considerable energy and commitment to their work. However, the IOM committee also cautioned that the competing personal and professional interests of board members, arising from their representing institutions potentially benefiting from CIRM grants, prevented them from providing independent oversight and introduced potential bias into their decision-making. It recommended that CIRM revise its definitions of conflict of interest to recognize conflicts arising from nonfinancial interests and reconstitute the ICOC to have a majority of members independent of such ties (Institute of Medicine 2013, 7–9, 68–70). CIRM did not implement this recommendation, arguing that doing so would have required amending the State constitution, but CIRM did adopt a policy whereby members of the ICOC with an interest in an application had to recuse themselves from the review and funding decisions. This policy change did not satisfy many of CIRM’s critics. To underscore the seriousness of the potential conflict of interest issue, roughly 90 percent of the $2.7 billion in awards CIRM had made as of November 2019 were to institutions with representation on the ICOC (Jensen 2019). This issue has reemerged as CIRM is anticipating a vote on a new initiative for its renewal. The initial draft of the proposition, again written by Robert Klein, proposes to expand the ICOC to 35 persons, with most of the new members from hitherto unrepresented academic institutions and patient advocacy groups. This would likely make the ICOC even more unwieldy. The draft seeks to resolve the conflict of interest issue by instructing the ICOC to adopt NAS conflict of interest guidelines (Jensen 2019). However, the NAS is not a funding institution, nor does it have a standing committee serving as a board with a role comparable to the ICOC. As might be anticipated, the expansion of the already large ICOC and its proposed role in the draft proposition have critics. The ICOC has three policy-setting working groups: a 23-member Scientific and Medical Research Funding committee (also known as the Grants Working Group), an 11-member Scientific and Medical Research Facilities committee, and a 19-member Scientific and Medical Accountability Standards committee. The Scientific and Medical Research Funding Working Group is tasked with reviewing and making recommendations to the Application Review Subcommittee of ICOC with respect to funding research proposals, including consideration of the scientific merit of research facilities, grants, and requests for loans. The Grants Review

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membership includes the ICOC Chair (ex-officio), seven representatives from among the ten disease advocacy group members on the ICOC, and more than 100 stem cell science experts from outside California with a wide range of expertise, 15 of whom participate in each review, depending on their areas of expertise. The Scientific and Medical Research Funding Working Group ranks the proposals with numerical scores and recommends a subset of applications to CIRM based on the scientific merits of the proposals. The specialists do not have voting privileges (California Institute for Regenerative Medicine, n.d.). The second working group, the Facilities Working Group, consists of the Chairperson of the ICOC, members of the Scientific and Medical Research Funding Working Group, and four real estate specialists from California. It makes recommendations to the ICOC on interim and final criteria, requirements, and standards for applications for, and on the awarding of grants and loans for, buildings, building leases, and capital equipment (California Institute for Regenerative Medicine, n.d.). The third working group, the Scientific and Medical Accountability Standards Working Group, has a mandate to make recommendations to the ICOC on scientific, medical, and ethical standards pertaining to stem cell research and compliance with adopted standards. It incorporates outside ethicists for this purpose. Once ICOC adopts policies recommended by the Standards Working Group, they become part of CIRM’s formal regulations. The group has also created guidance documents to interpret the formal regulations. Related to their work, CIRM has held workshops and meetings to explore in-depth scientific and policy issues within the fields of stem cell research and regenerative medicine and issued reports summarizing these workshops. However, the findings from these workshops have not usually been adopted as part of CIRM’s own standards. When initially formulated, CIRM’s regulations were intended to encourage research institutions and researchers to develop best practices for ethical conduct of human embryonic stem cell research. The regulations have also sought to avoid imposing unnecessary regulatory burdens. Like the regulations adopted by other state pluripotent stem cell funders, many of the CIRM regulations reflect the early concerns of the field; and, like them, they stress the importance of informed and voluntary consent from prospective donors of oocytes and embryos (Lomax, Hall, and Lo 2007). The Scientific and Medical Accountability Standards Working Group also identified human embryonic stem cell lines acceptable for research funded by CIRM, based on their ethical derivation. In addition, the Working Group drafted both CIRM-specific guidelines for the reporting of incidental findings by secondary researchers using induced pluripotent stem cell lines derived from

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living donors and model-informed consent documents for induced pluripotent cell research, but these guidelines were not informed by empirical studies. Disappointingly, bioethics has seemingly been relegated to a small role by CIRM. The Scientific and Medical Accountability Standards Working Group has not drafted regulations to provide substantive guidance for pluripotent stem cell research. Nor has it done so for the conduct of clinical trials by grantees or for the Alpha Clinics established by CIRM to conduct clinical trials. Moreover, the Scientific and Medical Accountability Standards Working Group does not seem to have played an ongoing role in CIRM’s review of proposed grants. In contrast with institutions engaged in pluripotent stem cell research, most of which require internal ethical review of proposed research, CIRM does not have the Scientific and Medical Accountability Standards Working Group or any other committee provide ethical review of proposals submitted for funding. The 2013 IOM Report commented on the absence of bioethics in CIRM’s work. It recommended that CIRM sponsor projects and offer new grant opportunities aimed specifically at identifying and addressing ethical, social, and regulatory issues surrounding stem cell–based research and that CIRM then use the information from these initiatives to strengthen its ethical standards for human subjects research. The Report pointed out that it is difficult for researchers to find appropriate funding for stem cell– specific ethics and policy work and that filling this gap would be well within CIRM’s budget capacity. Furthermore, it advised that expanding CIRM’s portfolio of project and grant opportunities related to bioethics would be consistent with, even mandated by, Proposition 71. The IOM Committee also recommended that, in light of CIRM’s stated goal, in its 2012 strategic plan, to initiate clinical trials research, the ICOC should adopt related ethical and regulatory standards for that purpose (Institute of Medicine 2013, 98– 100). Again, CIRM did not adopt these recommendations, but it is unclear as to why it did not do so. CIRM of course has a professional staff, many of whom have served the agency since its inception. CIRM is restricted by Proposition 71 to have no more than 50 staff, excluding members of the working groups. Of the $3 billion made available through Proposition 71, approximately $2.75 billion was set aside to be awarded for research, facilities, and training. The remainder was then earmarked for staff and administration (California Institute for Regenerative Medicine, n.d.). CIRM is therefore unusual in how small its staff is for an organization spending some $300 million annually and in how little it spends on administration and overhead.

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CIRM’s Investments in Training CIRM’s statement of mission is “To support and advance stem cell research and regenerative medicine under the highest ethical and medical standards for the discovery and development of cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease and injury” (California Institute for Regenerative Medicine, n.d.). In support of this mission, the ICOC adopted its first strategic plan at the end of 2006 to guide the first five years of CIRM’s programs. The primary goal for this initial phase was to establish a foundation for California’s leadership in stem cell research and development. It had four main components: to develop appropriate laboratory facilities, to fund training programs, to support basic research in stem cell biology, and to invest in programs focused on research on a broad range of diseases. Much of the emphasis was on developing the basic science of stem cells (Institute of Medicine 2013). CIRM has made a major investment in training to develop a corps of well-trained stem cell researchers and to make other academics more aware of the possibilities of the field. As of 2020, it had invested $220 million in education (Millan 2020). CIRM has offered grants to California public colleges and universities and non-profit academic and research institutions to foster training at a variety of levels: pre-doctoral students, post-doctoral fellows, and clinical fellows. Initially, the goal was to provide training for a wide variety of scientists at different stages of their careers and from scientifically diverse backgrounds, including relevant fields of biology (developmental biology, cell biology, neurobiology, molecular biology), clinical training (medicine, surgery, neurology, cardiology, psychiatry, etc.), and bioengineering, as well as ethics and law. All training programs were required to offer one or more classes in stem cell biology and its applications to health and disease along with opportunities for either laboratory work under the direction of a mentor in stem cell biology or clinical training in a field closely related to stem cell research. To participate in the training program, institutions were also required to offer a course in the social, legal, and ethical implications of stem cell research, likely because the development of pluripotent stem cell lines from embryos was initially a contentious issue. Training grants were offered for up to three years (California Institute for Regenerative Medicine, n.d.). To be able to encourage and facilitate the career development of physician scientists in the critical early stages of their careers as independent investigators and faculty members, CIRM instituted new faculty physician scientist awards that provided salary and research support for up to five years (California Institute for Regenerative Medicine, n.d.). In addition, CIRM has sponsored

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two internship programs – SPARK (Summer Program to Accelerate Regenerative medicine Knowledge), for high school students, and Bridges, for undergraduate and master’s students – located at major academic research institutions in the state, to help cultivate students’ interest in stem cell science (California Institute for Regenerative Medicine, n.d.). As of February 2020, 482 students had participated it SPARK and 1373 in Bridges (Millan 2020). Sponsoring frequent workshops and meetings to update scientific staff and CIRM grantees about developments in particular areas of stem cell and related research and offering grant funding for conferences on a stem cell–related topic have constituted another component of CIRM’s education and training programs. These workshops and conferences have addressed such topics as “Stem Cells for Huntington’s Disease,” “[Induced Pluripotent Stem Cells]: A Decade of Progress and Beyond,” ““Myelin Through the Ages,” “Delivery of Stem Cell Therapeutics to Patients,” and “Neural Stem Cell Relays for Severe Spinal Cord Injury.” The Alpha Stem Cell Clinics, described later in the chapter, also hold annual symposia about developments in clinical trials (California Institute for Regenerative Medicine, n.d.).

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CIRM’s Investments in Infrastructure A second key aspect of CIRM’s initial plan was the investment in research facilities to accommodate the influx of stem cell researchers in California in response to CIRM’s training grants and research programs. CIRM’s major facilities program enabled the building of state-of-the-art spaces for carrying out stem cell research in many academic institutions throughout the state. The agency’s initial investment of $271 million leveraged an additional $543 million in private donations and institutional commitments toward the construction of 12 major buildings. The list of infrastructure grants from CIRM and the additional resources the grants generated is as follows: x Buck Institute for Research on Aging, Regenerative Medicine Research Center, Novato, California, total of $36.5 million of which $20.5 million was from CIRM; x Sanford Consortium for Regenerative Medicine, University of California San Diego, total of $127 million of which $43 million was from CIRM; x Stanford University, Lorry I. Lockey Stem Cell Research Building, total of $200 million of which $43.6 million was from CIRM;

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x University of California, Berkeley, Li Ka Shing Center for Biomedical and Health Sciences, total of $257 million of which $20 million was from CIRM; x University of California, Davis, Institute for Regenerative Cures, total of $62 million of which $20 million was from CIRM; x University of California, Irvine, Sue and Bill Gross Stem Cell Research Center, total of $80 million of which $27.2 million was from CIRM; x University of California, Los Angeles, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, total of $43 million of which $19.8 million was from CIRM; x University of California, Merced, Stem Cell Instrumentation Foundry, total of $7 million of which $4.4 was from CIRM; x University of California, San Francisco, Ray and Dagmar Dolby Regeneration Medicine Building, total of $123 million of which $34.9 million was from CIRM; x University of Southern California, Eli and Edythe Broad CIRM Center for Regenerative Medicine and stem Cell Research, total of $80 million of which $27 million was from CIRM; x University of California, Santa Cruz, Institute for the Biology of Stem Cells, total of $83.7 million of which $7.2 million was from CIRM; x University of California, Santa Barbara, Center for Stem Cell Biology and Engineering, total of $6.4 million of which $3.1 million was from CIRM (California Institute for Regenerative Medicine, n.d.). As this list indicates, the major campuses of the University of California and Stanford University were beneficiaries of CIRM’s infrastructure building grants. CIRM thereby established a network of stem cell research centers throughout the state of California.

CIRM’s Investments in Scientific Research CIRM’s early emphasis was on funding research to examine and discover the fundamentals of cell biology. It then transitioned to an emphasis on translating these findings in specific disease areas toward applications for treatment. The CIRM Basic Biology Awards program funded research grants to investigate basic mechanisms underlying stem cell biology, cellular plasticity, and cellular differentiation. CIRM has several types of research grants. Discovery grants are for basic or early-stage research that

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explores new and groundbreaking stem cell treatments and technologies. In the translational research category, CIRM takes the best candidate therapies identified through discovery research and then supports them along the steps needed to advance them to the clinical development stage. Clinical research, the third category, involves CIRM support for testing in patients, hopefully to obtain approval from the Food and Drug Administration. As of 2018, CIRM had invested $905 million in discovery-stage research, $343 million in translational-stage research, and $647 million in clinical-stage research (California Institute for Regenerative Medicine, n.d., 5). The approved budget for 2019 included another $20 million for translational research and $123 million for clinical trials (California Institute for Regenerative Medicine, n.d., 24). As of 2018, CIRM had funded some 1,000 projects at more than 70 institutions in California (California Institute for Regenerative Medicine, n.d., 12). CIRM has also been able to tap other resources for the projects it supported. As of 2018, its projects had attracted some $1 billion in cofunding, mostly from industry, and $1.6 billion in partnership funding to help advance projects (California Institute for Regenerative Medicine, n.d., 6). CIRM has been concerned to involve the private sector through public– private partnerships in order to overcome what it has perceived as insufficient interest from industry in stem cell treatment technologies and to facilitate their efficient advancement to the marketplace. CIRM has also realized that it does not have sufficient resources to fund prospective therapies through the three stages of clinical trials or the manufacturing capability to manufacture cell-based therapies in the numbers required for Phase Three clinical trials and to bring them to market (California Institute for Regenerative Medicine, n.d., 28, 46). In another type of partnership, in 2019 CIRM entered into a strategic partnership with the National Institutes of Health (NIH) to co-fund cell and gene therapy programs under the NIH Cure Sickle Cell initiative. Using CIRM’s resources and expertise in stem cell and regenerative research, the program will seek to accelerate development of therapies for sickle cell disease (Villa 2019a). As of March 2020, the CIRM website lists 1,030 grants: 1 preactive, 168 active, and 861 closed (California Institute for Regenerative Medicine, n.d.). These are distributed across five programs as follows: 74 Infrastructure, 567 Discovery, 88 Clinical (including 46 Clinical Trial Stage Projects), 95 Translation, and 206 Education. Infrastructure grants include those discussed in the previous section and the Alpha clinics discussed in the next. Education grants include conferences and the student internships discussed previously in this chapter. Of the Discovery program grants, 110 were Basic Biology, 58 and 39 were Quest or Inception Awards, and 75

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were Early Translational. Of the Project grants in the Translation program, 1 was Diagnostic Translational, 1 was Tool Translational, and 32 were Therapeutic Translational. Additionally, 21 of the Clinical program grants were for Late Stage Preclinical Projects, which were presumably in the process of preparing for an investigational new drug (IND) application with the FDA. Some confusion may arise from the difference between the 46 Clinical Trial Stage Project grants and the 60 clinical trials reported on the CIRM website (California Institute for Regenerative Medicine, n.d.). Most of the Clinical Trial Stage Project grants were associated with one (and only one) of these clinical trials, the exceptions being two grants with end dates later than 2020. There were also two clinical trials not associated with such grants—namely, the Geron and ViaCyte trials discussed elsewhere in this chapter. Of the 14 other clinical trials not directly funded by Clinical Trial Stage Project grants, 14 were funded by grants of other types: 6 by Disease Team Therapy Development – Research grants, 5 by Disease Team Therapy Development III grants, 2 by Strategic Partnership III Track A grants (all in the Clinical program), and 1 by a Disease Team Research I grant (in the Translation program). Not all of the funded scientific research projects utilized pluripotent stem cells, but more recent grants increasingly support such projects. Of the 62 Translation and Late Stage Preclinical Projects (excluding Disease Team grants), just a bit over one third (24) were based on pluripotent stem cells. Thirteen used human embryonic stem cells, 1 a combination of human embryonic stem cells and induced pluripotent stem cells, and 10 induced pluripotent stem cells. Most of the others utilized some form of adult stem cells. In contrast, the early discovery-stage research projects had a greater tilt toward pluripotent stem cells, particularly induced pluripotent stem cells. Of the 493 Discovery grants (excluding New Faculty and Research Leadership grants), 98 worked with induced pluripotent stem cells, 56 with both induced pluripotent stem cells and human embryonic stem cells, and 192 with human embryonic stem cells. These are far more than worked with adult stem cells (77) and with other stem cell types (16), though some additional projects worked with both pluripotent and nonpluripotent stem cells. These trends suggest the maturing of the pluripotent stem cell research field. To promote research with human induced pluripotent stem cells and the use of induced pluripotent stem cells as tools for disease modeling and drug discovery, CIRM created a large induced pluripotent stem cell bank. CIRM’s iPSC (induced pluripotent stem cell) Repository houses a collection of stem cells from thousands of individuals, some healthy and

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others with various types of diseases or disorders. The Broad Institute’s Stanley Center for Psychiatric Research and Harvard University are currently using the Repository to study neurological disorders, such as autism (California Institute for Regenerative Medicine, n.d., 14). As of the end of 2019, the research of eleven of the recipients of CIRM’s early-stage awards had progressed to clinical trials. The disease areas are varied: some relate to rare diseases such as polycythemia vera, a rare, chronic blood disorder, others common cancers including leukemia, melanoma, and brain cancer, and still others spinal cord injury (California Institute for Regenerative Medicine, n.d.). CIRM’s sponsored research portfolio suggests that it has not had a clear set of priorities as to which type of research, or which diseases, it decided to accord priority for funding. Instead, CIRM seems to have taken a more passive approach, agreeing to fund any type of promising research that was proposed to it that might lead to a therapeutic application. Moreover, CIRM does not acknowledge using any type of calculus in making that determination. Nor has CIRM had an independent outside scientific assessment of its portfolio. This lack of a strategic approach may be a reflection of its ample resources. Funding agencies with less money to spend generally need to set priorities and focus their spending accordingly. Instead, CIRM often seemed determined to spend as much money as possible as quickly as possible. That approach also seemed to apply to cell types and their applications. While CIRM was established to specifically focus on pluripotent stem cells, CIRM has not done so. Instead, it has supported research for a variety of types of cells and therapeutic approaches. This likely reflects the low number of pluripotent stem cell project proposals it received and the promise of new scientific approaches to gene therapy and gene editing not anticipated when CIRM was established. Also, it likely assumed that research using adult stem cells would have a quicker path to FDA approval.

CIRM’s Investments in Clinical Trials According to the CIRM website, the agency “funds clinical trials testing promising stem cell-based treatments for currently incurable diseases or disorders to help patients with unmet medical needs” (California Institute for Regenerative Medicine, n.d.). About a fourth of CIRM’s expenditures to date, $744 million as of February 2020, has been devoted to supporting clinical trials (Millan 2020). Most of these grants and loans were made between 2016 and 2019, as CIRM sought to accelerate the testing of candidate stem cell therapies in advance of returning to the voters for a $5.5

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billion renewal of funding. As of November 2019, CIRM had provided funding for 60 clinical trials (California Institute for Regenerative Medicine, n.d.). As noted in earlier chapters of this book, the development of cell therapies faces many hurdles and constraints including complex preclinical research issues, limited funding, an evolving regulatory landscape, lack of experience with the conduct of clinical trials among many of the researchers and institutions involved with pluripotent stem cell research, and manufacturing issues with replicating sufficient numbers of cells. In addition to providing funding, particularly for the less expensive early-stage clinical trials, CIRM has sought to address many of these issues for its grantees. Key to its commitment to accelerating the translation of stem cell therapies, CIRM launched the Alpha Stem Cell Clinics (hereafter Alpha) Network in 2015 to provide the infrastructure and clinical trial capacity for cell-based clinical trials in California once they received Investigational New Drug (IND) approval from the Food and Drug Administration (FDA). The Alpha network is a series of clinical sites at five academic medical centers in California: City of Hope, University of California Davis, University of California Irvine and University of California Los Angeles, University of California San Diego, and University of California San Francisco. These sites are intended to build and implement an infrastructure to support launching and running high-quality stem cell clinical trials. While each Alpha Stem Cell Clinic operates independently, they can also leverage the collective resources and knowledge of the network. One initiative of the network is to develop resources for explaining cell-based clinical trials and their risks to patients to enable them to make informed decisions about participation. Other CIRM-supported institutions facilitate the manufacturing, processing, and delivery of cells in a timely manner for members of the Alpha network (Jamieson et al. 2018). As of the end of 2019, the Alpha network had conducted or facilitated more than 90 trials, not all of them funded or supported by CIRM (California Institute for Regenerative Medicine, n.d.). The City of Hope National Medical Center located near Los Angeles has been CIRM’s leading Alpha clinic. To complement the Alpha network, CIRM established a Stem Cell Center to support manufacturing, preclinical safety testing, and other activities needed to apply to the FDA for approval to start a clinical trial. The Stem Cell Center includes the Translating Center, which provides preclinical research services to entities developing stem cell–based treatments, with an initial emphasis on CIRM-funded projects. One of its roles is management of a preclinical data package suitable for inclusion in an IND application to the FDA to start clinical trials. The Stem Cell Center

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also has an Accelerating Center to provide logistical, operational, and consultative services to clinical trial sponsors and clinics, with the goal of accelerating the regulatory review process and the conduct of high-quality stem cell treatment clinical trials. Its services include regulatory management, clinical trial planning, operations and management, and the provision of data management systems. CIRM has awarded a contract to IQVIA, a private sector company with expertise in applying big data, innovative technology, and contract research services to health care, to manage both the Translating Center and the Accelerating Center (California Institute for Regenerative Medicine, n.d.). To promote significant stem cell science headed to the clinic, CIRM also provides other forms of support through the establishment of two types of advisory panels to partner with the researchers. When the CIRM Governing Board approves a project, CIRM establishes a translational advisory panel to aid the scientists conducting the studies to develop an approach that holds promise for clinical applications. The second type of panel, the clinical advisory panels, help CIRM-supported researchers plan clinical trials, troubleshoot potential pitfalls, and work collectively to overcome any problems. The clinical advisory panels consist of at least three advisors: a CIRM science officer, an independent stem cell expert, and a patient advocate (California Institute for Regenerative Medicine, n.d., 16). In May 2011, CIRM funded its first clinical trial, which was also the first first-in-human trial of a therapy developed from human embryonic stem cells. Some eight and a half years later, in November 2019, CIRM’s Board approved funding for its sixtieth clinical trial. CIRM’s initial 60 clinical trials covered 10 different disease areas. The greatest number of trials were of candidate therapies for blood cancers, other blood diseases, and solid cancers. Together, these three categories represent slightly more than half of all CIRM-assisted clinical trials. The distribution of the disease areas of the 60 clinical trials is as follows: blood cancers, 18 percent; other blood diseases, 20 percent; solid cancers, 15 percent; neurological applications, 11 percent; kidney disorders, 11 percent; eye disorders, 6 percent; diabetes, heart diseases, and HIV-AIDs, 5 percent each; and bone diseases, 4 percent (California Institute for Regenerative Medicine, n.d.). As might be expected, the majority of these 60 clinical trials are early-phase trials, primarily Phase 1 trials designed to evaluate tolerability, dosage, and safety and not to assess efficacy (as do later stage trials). Of the 60 CIRM-supported trials, 46 were either Phase 1 or Phase 1/2, which are trials that can integrate the planning and transition from Phase 1 to Phase 2. Most of the CIRM-supported Phase 1 trials were intended to enroll small

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numbers of participants, ranging from six to 18 patients, but there are a few trials with as many as 57, 112, or even 156 patients targeted. Eight of the CIRM-supported trials have progressed to Phase 2, and four have begun Phase 3 recruiting or are in the process of conducting a Phase 3 trial. These latter trials are the BrainStorm Cell Therapeutics’ trial for amyotrophic lateral sclerosis (ALS), Medeor Therapeutics’ trial for kidney disease, and two of Humacyte’s candidate therapies for kidney failure. Two CIRMsupported Phase 3 trials have been closed: Caladrius Biosciences terminated testing during a Phase 3 trial for an experimental therapy for melanoma skin cancer, ostensibly for business reasons. ImmunoCellular Therapeutics suspended its Phase 3 trial of a therapeutic for glioblastoma brain cancer until it could raise additional funds (California Institute for Regenerative Medicine, n.d.). Chapter Four noted the difficulty of raising sufficient funds for the testing of the larger patient cohorts required in Phase 3 testing. CIRM has supported clinical trials conducted both by academic institutions and by biotechnology companies in California. CIRM has provided funding for conducting clinical trials to the City of Hope, the University of Southern California, Stanford University, the University of California San Francisco, the University of California San Diego, and the University of California Davis. It has also supported clinical trials conducted by Cedars-Sinai Medical Center, Children’s Hospital of Los Angeles, and St. Jude Children’s Research Hospital. A substantial number of the CIRM-supported clinical trials have also been conducted by small biotechnology companies. According to the listing on CIRM’s Clinical Dashboard, 24 of the grants – more than a third – made to support clinical trials went to private companies. Several of the companies – Forty Seven Inc., Capricor Inc., Humacyte, Caladrius, jCyte, and ViaCyte – received two grants or loans each (California Institute for Regenerative Medicine, n.d.). Although the campaign to support Proposition 71 stressed the need to have public funding in order to develop therapeutics from human embryonic stem cells, only five of the clinical trials CIRM has supported to date have derived their therapeutic applications from human embryonic stem cells. Moreover, none of the CIRM-supported clinical trials has as yet employed candidate therapies developed from human induced pluripotent stem cells. Although the text of Proposition 71, which became the basis of the law in California governing stem cell research, emphasizes pluripotent stem cell research and progenitor cell research, it also supports stem cell research in general. Importantly, Proposition 71 instructs CIRM to make maximum use of resources by giving priority to the stem cell research with the greatest potential for therapies and cures (Institute of Medicine 2013, Appendix C: Proposition 71). Anxious to sponsor clinical trials, CIRM

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apparently was not given the option of funding additional pluripotent stem cell clinical trials. The first clinical trial CIRM funded, in 2011, through providing a loan was Geron Corporation’s Phase I trial to assess GRNOPC1, a human embryonic stem cell–derived candidate therapy for treatment of severe spinal cord injuries. However, as will be noted in Chapter Six, after five patients were injected, apparently without suffering serious adverse effects or evidence of immune rejection of GRNOPC1 even after the withdrawal of the immunosuppresive drug, Geron halted the trial. Apparently, despite considerable hype from the Geron Corporation prior to the trial, none of the participants in the trial experienced a meaningful improvement in mobility. In a statement, however, the company claimed that its decision was motivated by capital scarcity and uncertain economic conditions and not by the lack of promise of stem cell therapies. Geron’s then-recently appointed Chief Executive Officer, who apparently had a different set of priorities than his predecessor, indicated that the company had decided to focus on its cancer therapies that were further along in development (Chapman and Scala 2012). Geron did repay the funding it had received to CIRM. Geron eventually transferred its stem cell research and related intellectual property assets to Asterias Biotherapeutics, another small California-based biotechnology company. Asterias, now Lineage Cell Therapies Inc., has also received funding from CIRM for its Phase 1/2a trial, with an expanded number of patients and approval from the FDA for testing on more types of spinal cord injuries. Asterias/Lineage Cell Therapies has now treated 25 patients with no serious side effects and some encouraging results (McCormack 2018c). Another CIRM grant for a human embryonic stem cell–derived therapy went to researchers at the University of Southern California. It is a Phase I trial of a therapeutic being tested for age-related dry macular degeneration. The eye is a popular target for pluripotent stem cell researchers because it is accessible and immune privileged and therefore does not need immunosuppressants. Two other awards were given to Viacyte Inc. for its two trials of therapeutics for Type 1 diabetes. Viacyte is currently testing a human embryonic stem cell–derived therapeutic to replace lost beta cells in persons with diabetes. The therapeutic is being administered by inserting it in a small pouch that is transplanted under the patient’s skin to protect it from the immune system. Other clinical trials receiving CIRM’s support use adult stem cells of various types from patients and donors, many of which have been genetically modified. The two most common types of adult stem cells in

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these applications are hematopoietic stem cells and mesenchymal stem cells. The clinical trials also involve antibodies, chimeric antigen receptors (CAR T therapeutics), a type of cancer immunotherapy, proteins, zinc finger nucleases, an artificial restriction enzyme engineering to target specific DNA sequences, monoclonal antibodies, and drugs designed to either enhance or suppress the activity of cells. To provide some examples, the University of San Francisco has a Phase 1 clinical trial using hematopoietic stem cells from the mother’s bone marrow to treat babies in the womb with alpha thalassemia major, a blood disorder that is almost always fatal. BrainStorm Cell Therapeutics is beginning a Phase 3 trial using mesenchymal stem cells taken from patients’ own bone marrow and modified in the laboratory to boost production of neurotrophic factors to support and protect neurons in patients with ALS. The University of California San Diego is testing the antibody cirmtuzumab to disable a protein and thereby slow the growth of leukemia in order to make it more vulnerable to anti-cancer drugs. Stanford University is recruiting patients for a B-cell leukemia trial with chimeric antigen receptor (CAR) T-cell therapy that works by isolating patient’s own T immune cells and then genetically engineering them to recognize a protein on the surfaces of cancer cells and thereby trigger their destruction. Capricor Inc. has completed a Phase 2 trial for patients with heart disease associated with Duchenne muscular dystrophy using donor cells derived from the heart. Capricor recently closed a second Phase 2 trial, using allogeneic cardiacderived stem cells to treat suffering from a myocardial infarction, after it failed to achieve its primary goal. The City of Hope is recruiting patients for a Phase 1 trial in which zinc finger nucleases modified autologous hematopoietic stem progenitor cells along with escalating doses of busalfan will be applied to patients with HIV/AIDS. Angiocrine Bioscience Inc., recipient of CIRM’s fiftieth clinical trial award, plans to test genetically engineered cells derived from cord blood to see if they can help alleviate or accelerate recovery from the toxic side effects of chemotherapy in people undergoing treatment for lymphoma and other aggressive cancers of the blood and lymph systems.

Reflections CIRM has played a central role in the development of the pluripotent stem cell field and enabled California to become the global leader in stem cell research. As the stem cell field has progressed, CIRM has remained at its center, contributing to its development and shaping its future. Since its inception, CIRM has funded more than 1,000 projects at some 70

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institutions in California. CIRM’s funding has in some cases made this critical research possible and in others speeded it up. CIRM funding has resulted in many scientific discoveries that may lead to cures for currently incurable diseases suffered by thousands of people. It has also facilitated the development of stem cell–based therapeutics by supporting 60 clinical trials. The importance of CIRM-sponsored research is evinced by the publication of over 3,000 articles in peer-reviewed scientific journals, many of them top journals in their fields, by researchers CIRM supported (Goldstein, Anderson, and Burnham 2019). There are promising results from investigational therapies in various of the clinical trials CIRM has funded. CIRM has reported that Capricor Therapeutics has presented positive results from a clinical trial related to treatment for Duchenne muscular dystrophy, a genetic disorder that leads to progressive muscle degeneration and weakness. Early results of the trial demonstrated meaningful improvements in both teens and young men in advanced stages and in older patients (Villa 2019b). There was encouraging news about a CIRM-funded Phase 1/2a clinical trial targeting dry age-related macular degeneration as well. Of the five patients enrolled, four maintained their vision in the treated eye, two showed improvement in the stability of their vision, and one attained a 17-letter improvement in their vision in a reading chart. The trial is now being expanded to more patients (McCormack 2018a). CIRM has also reported encouraging progress from the Geron/Asterias/Lineage clinical trial to help people with recent spinal cord injuries resulting in paralysis from the neck down by implanting oligodendrocyte progenitor cells (OPCs) (McCormack 2018c). OPCs play an important role in supporting and protecting nerve cells in the central nervous system. Five of the six Cohort 2 patients achieved at least two motor levels of improvement over baseline on at least one side. A year later, with the expansion of the trial to 25 patients, none experienced adverse changes; 95 percent of patients had recovered at least one motor level on at least one side; and a third of the subjects recovered two or more motor levels on at least one side (McCormack 2019a). But these are still early trials a long way from yielding FDA-approved therapies. CIRM also points to its beneficial economic impact to the people of California. The campaign to fund Proposition 71 had claimed that the initiative would create thousands of jobs and potentially return the state’s investment many times over. One projected source of this return would be royalties from the discoveries paid over the next 35 years. So far, CIRM has received a single royalty payment of $190,000 from the City of Hope medical research center stemming from a $5.2 million award for research for a potential therapy for glioblastoma, one of the deadliest forms of brain

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cancer (Jensen 2018). This is a small, perhaps insignificant return on investment, but many of the potential therapies in which CIRM has invested are still in development and more royalties may eventually be forthcoming. In terms of measuring CIRM’s economic benefit, CIRM’s investment has enabled it to leverage another $3.2 billion for CIRM-supported programs. This includes $1 billion in co-funding from institutions, industry, or investors who join with CIRM to fund a specific project; $1.6 billion in partnership funding independent of CIRM funding to help advance a project, and $541 million in additional funding from investors (California Institute for Regenerative Medicine, n.d., 6). Much of this is private and corporate funding. In addition, an independent analysis of the economic impacts of CIRM by two researchers at the Schaeffer Center for Health Policy and Economics at the University of Southern California, issued in October 2019, found that CIRM’s investments and activities had resulted in increases in economic output, employment, and tax revenues. The report estimated that the total quantified economic impacts of CIRM on the California economy were $10.7 billion of additional gross output (sales revenue), $641.3 million of additional state and local tax revenues, an additional $726.6 million of federal tax revenues, and 56,549 additional full-time equivalent jobs, half of which offer salaries considerably higher than the state average (Wei and Rose 2019, ES-1). When assessing CIRM’s contributions to the regenerative medicine field, it might be asked why CIRM, which was ostensibly established to promote embryonic stem cell research, has not had more of a tilt toward investing in pluripotent stem cell research. As noted above, CIRM has only supported a limited number of clinical trials with pluripotent stem cells. Moreover, none of CIRM’s most recent grants – the ten clinical trials funded in 2019 – use a therapeutic developed from pluripotent stem cells. My informal discussions with staff of CIRM in June 2018 affirmed that CIRM has been open, even enthusiastic, to funding research and clinical trials with therapies developed from human embryonic stem cells when given the opportunity to do so. Apparently, the field has not yet progressed to the point where many other clinical trials with therapeutics derived from pluripotent stem cells are being proposed to CIRM for funding. Because CIRM has been under pressure to have promising therapies to take to the voters, it apparently decided to focus less on the source of the cells and more on the potential of the therapies and their likelihood of gaining FDA approval sooner. Moreover, promising new approaches to cell editing and gene therapy became available that were not anticipated in 2004. Nevertheless, it is disappointing that more of CIRM’s investment in research and clinical trials was not focused on the pluripotent stem cells

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that provided the rationale for Proposition 71 and that CIRM was not more active in this regard. As noted above, CIRM’s staff did not have sufficient prospective pluripotent stem cell projects proposed, particularly clinical trial projects, in which to invest its funds. However, as noted in the above analysis of all active CIRM grants made as of November 2019, CIRM has a substantial number of pluripotent stem cell research projects in its pipeline. Presumably, if its funding is renewed in 2020, many of these will progress to clinical trials. In supporting Proposition 71, most Californians expected to speed the delivery of stem cell treatments and cures to patients with unmet medical needs. Has CIRM done so? Crucially, none of the candidate therapies CIRM has supported has as yet received FDA approval to be marketed. It is noteworthy, though, that six of the first 40 projects to which the FDA awarded Regenerative Medicine Advanced Therapy (RMAT) designation received CIRM funding (McCormack 2019b). These projects include Humacyte’s candidate therapy for kidney failure, JCyte’s candidate therapy for retinitis pigmentosa, and Asterias’ candidate therapy for spinal cord injury. Only the last was developed from embryonic stem cells. Additionally, Orchard Therapeutics and UCLA have hopes that their therapy for severe combined immunodeficiency (SCID), developed with $50 million from CIRM among other sources, will receive RMAT designation in 2020 (Jensen 2020). RMAT designation provides an expedited FDA pathway that enables sponsors to apply for priority review and therefore get faster approval. CIRM has some therapies it claims as successes because they cured or significantly improved the health status of a single or a small group of individuals. These include recipients of therapies for X-CGD, a rare immune disorder (California Institute for Regenerative Medicine, n.d., 7); for two forms of SCID, a life-threatening immune disorder that leaves those affected individuals unable to fight infections and often having to remain in an isolation unit (California Institute for Regenerative Medicine, n.d., 15, 21); and for retinitis pigmentosa, which gradually causes blindness (California Institute for Regenerative Medicine, n.d., 9); as well as a transplant to a fetus in the womb suffering from alpha thalassemia major, an usually fatal blood disorder (Penumetcha 2018); and a paralyzed patient regaining the use of his arms and hands (McCormack 2018b). It is unclear whether CIRM’s record of making California the leader of the regenerative medicine field and its role in funding an increasing number of potentially transformative medical treatments will be enough to convince the people of California to approve a second tranche of $5.5 billion in state funding for its stem cell work. As someone supportive

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of the pluripotent stem cell field, I believe it would be very unfortunate if CIRM does not receive this funding. The regenerative medicine field may be on the threshold of important breakthroughs that will be unlikely to occur without CIRM’s continued investments and leadership.

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References Acosta, Nefi D., and Sidney H. Golub (2016) “The New Federalism: State Policies Regarding Embryonic Stem Cell Research.” The Journal of Law, Medicine & Ethics 44 (3): 419–36. Adelson, Joel W., and Joanna K. Weinberg (2010) “The California Stem Cell Initiative: Persuasion, Politics, and Public Science.” American Journal of Public Health 100 (3): 446–51. Allday, Erin, and Joaquin Palomino (2018) “Lofty Promises, Limited Results.” San Francisco Chronicle, September. https://projects.sfchronicle.com/2018/stem-cells/politics/. Burgin, Eileen (2010) “Human Embryonic Stem Cell Research and Proposition 71: Reflections on California’s Response to Federal Policy.” Politics and the Life Sciences 29 (2): 73–95. California Institute of Regenerative Medicine (n.d.) “2009/2010 Strategic Plan Update: Accelerating the Opportunity for Cures” (Accessed 23 May 2020). https://www.cirm.ca.gov/sites/default/files/files/agenda/081909_item_ 18.pdf. California Institute for Regenerative Medicine (n.d.) “2018 Annual Report: Something Better Than Hope” (Accessed 23 May 2020). https://www.cirm.ca.gov/printpdf/about-cirm/2018-annual-report. California Institute for Regenerative Medicine (n.d.) “Active Awards Portfolio Dashboard” (Accessed 23 May 2020). https://www.cirm.ca.gov/active-awards-portfolio. California Institute for Regenerative Medicine (n.d.) “All CIRM Grants” (Accessed 23 May 2020). https://www.cirm.ca.gov/grants. California Institute for Regenerative Medicine (n.d.) “Alpha Stem Cell Clinics Trials” (Accessed 23 May 2020). https://www.cirm.ca.gov/patients/alpha-clinics-network/alpha-clinicstrials. California Institute for Regenerative Medicine (n.d.) “Beyond CIRM 2.0: Proposed Strategic Plan: 2016 & Beyond” (Accessed 23 May 2020). https://www.cirm.ca.gov/sites/default/files/files/agenda/151217_Agend a_7_CIRM_StratPlan_final_120815.pdf.

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California Institute for Regenerative Medicine (n.d.) “Cell and Gene Therapy Center” (Accessed 23 May 2020). https://www.cirm.ca.gov/researchers/cell-and-gene-therapy-center. California Institute for Regenerative Medicine (n.d.) “Clinical Trials Based on CIRM Grants” (Accessed 23 May 2020). https://www.cirm.ca.gov/ourprogress/clinical-trials-based-cirm-grants. California Institute for Regenerative Medicine (n.d.) “Funding Clinical Trials” (Accessed 23 May 2020). https://www.cirm.ca.gov/clinical-trials. California Institute for Regenerative Medicine (n.d.) “Internship Programs” (Accessed 23 May 2020). https://www.cirm.ca.gov/our-impact/internshipprograms. California Institute for Regenerative Medicine (n.d.) “New Faculty Physician Scientist” (Accessed 23 May 2020). https://www.cirm.ca.gov/ourfunding/research-rfas/new-faculty-physician-scientist. California Institute for Regenerative Medicine (n.d.) “Our Governing Board” (Accessed 23 May 2020). https://www.cirm.ca.gov/board-and-meetings/board. California Institute for Regenerative Medicine (n.d.) “Program and Building Infrastructure” (Accessed 23 May 2020). https://www.cirm.ca.gov/ourimpact/creating-infrastructure. California Institute for Regenerative Medicine (n.d.) “Scientific and Medical Research Funding Working Group” (Accessed 23 May 2020). https://www.cirm.ca.gov/node/3429. California Institute for Regenerative Medicine (n.d.) “Scientific & Medical Facilities Working Group” (Accessed 23 May 2020). https://www.cirm.ca.gov/node/3432. California Institute for Regenerative Medicine (n.d.) “Training Grant I-1” (Accessed 23 May 2020). https://www.cirm.ca.gov/our-funding/researchrfas/training-grant-i-1. California Institute for Regenerative Medicine (n.d.) “Where CIRM Funding Goes” (Accessed 23 May 2020). https://www.cirm.ca.gov/about/wherecirm-funding-goes. Chapman, Audrey R., and Courtney C. Scala (2012) “Evaluating the Firstin-Human Clinical Trial of a Human Embryonic Stem Cell-Based Therapy.” Kennedy Institute of Ethics Journal 22 (3): 243–61. Goldstein, Lawrence S. B., Aileen Anderson, and Malin Burnham (2019) “Commentary: Why California’s Landmark Stem Cell Agency Deserves More Funding.” Bernie Siegel’s World Stem Cell Summit Blog, September. https://www.worldstemcellsummit.com/2019/09/25/commentary-whycalifornias-landmark-stem-cell-agency-deserves-more-funding/.

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Institute of Medicine (2013) The California Institute for Regenerative Medicine: Science, Governance, and the Pursuit of Cures. Washington, DC: The National Academies Press. https://doi.org/10.17226/13523. Jamieson, Catriona H. M., Maria T. Millan, Abla A. Creasey, Geoff Lomax, Mary E. Donohoe, Mark C. Walters, Mehrdad Abedi, Daniela A. Bota, John A. Zaia, and John S. Adams (2018) “CIRM Alpha Stem Cell Clinics: Collaboratively Addressing Regenerative Medicine Challenges.” Cell Stem Cell 22 (6): 801–5. Jensen, David (2018) “Will California’s $3 Billion in Stem Cell Spending Pay Off? First Royalty Check Arrives.” The Sacramento Bee, March. https://www.sacbee.com/latest-news/article201392069.html. Jensen, David (2019) “What’s Old Is New Again: Multibillion-Dollars in Stem Cell Spending and Conflicts of Interest.” California Stem Cell Report Blog, November. http://californiastemcellreport.blogspot.com/2019/11/whats-old-isnew-again-multibillion.html. Jensen, David (2020). Email to the author. Lomax, Geoffrey P., Zach W. Hall, and Bernard Lo (2007) “Responsible Oversight of Human Stem Cell Research: The California Institute for Regenerative Medicine’s Medical and Ethical Standards.” PLOS Medicine 4 (May): 1–3. https://doi.org/10.1371/journal.pmed.0040114. McCormack, Kevin (2018a) “Encouraging News About CIRM-Funded Clinical Trial Targeting Vision Loss.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, April. https://blog.cirm.ca.gov/2018/04/04/encouraging-news-about-cirmfunded-clinical-trial-targeting-vision-loss/. McCormack, Kevin (2018b) “Stem Cell Roundup: Jake Javier’s Amazing Spirit; TV Report Highlights Clinic Offering Unproven Stem Cell Therapies.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, May. https://blog.cirm.ca.gov/2018/05/25/stem-cellroundup-jake-javiers-amazing-spirit-tv-report-highlights-clinicoffering-unproven-stem-cell-therapies/. McCormack, Kevin (2018c) “Stem Cell Agency Board Approves 50th Clinical Trial.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, December. https://blog.cirm.ca.gov/2018/12/13/stem-cell-agency-board-approves50th-clinical-trial/. McCormack, Kevin (2019a) “One Year Later, Spinal Cord Therapy Still Looks Promising.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, May.

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https://blog.cirm.ca.gov/2019/05/03/one-year-later-spinal-cordtherapy-still-looks-promising/. McCormack, Kevin (2019b) “Time and Money and Advancing Stem Cell Research.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, August. https://blog.cirm.ca.gov/2019/08/20/timeand-money-and-advancing-stem-cell-research/. Millan, Maria T. (2020) “Something Better Than Hope: President’s Report.” California Institute for Regenerative Medicine; Report to ICOC. https://www.cirm.ca.gov/sites/default/files/files/agenda/200206%20Ag end%20Item%20%20%235%20FINAL%20President%27s%20Report _0.pdf. Penumetcha, Pallavi (2018) “CIRM Funded Study Results in the First Ever in Utero Stem Cell Transplant to Treat Alpha Thalassemia.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, June. https://blog.cirm.ca.gov/2018/06/04/cirm-funded-study-results-in-thefirst-ever-in-utero-stem-cell-transplant-to-treat-alpha-thalassemia/. Villa, Yimy (2019a) “CIRM & NHLBI Create Landmark Agreement on Curing Sickle Cell Disease.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, April. https://blog.cirm.ca.gov/2019/04/30/cirm-nhlbi-create-landmarkagreement-on-curing-sickle-cell-disease/. Villa, Yimy (2019b) “Encouraging Progress for Two CIRM Supported Clinical Trials.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, October. https://blog.cirm.ca.gov/2019/10/11/encouraging-progress-for-twocirm-supported-clinical-trials/. Wei, Dan, and Adam Rose (2019) “Economic Impacts of the California Institute for Regenerative Medicine (CIRM).” Schaeffer Center for Health Policy; Economics, Sol Price School of Public Policy, University of Southern California; Final Report (Accessed 23 May 2020). https://www.cirm.ca.gov/sites/default/files/CIRM_Economic%20Impa ct%20Report_10_3_19.pdf.

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CHAPTER SIX

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CLINICAL TRIALS WITH THERAPIES DERIVED FROM PLURIPOTENT STEM CELLS

Conducting human clinical trials is an essential step for developing therapies from pluripotent stem cells, but there are many ethical, regulatory, and scientific preconditions for beginning Phase I clinical trials responsibly – especially when they are first-in-human (FIH) trials, as many of the pluripotent stem cell–based clinical trials will be, at least initially. The level of risk to participants in clinical trials often correlates with the innovativeness of the therapy under consideration. As the International Society for Stem Cell Research (ISSCR)’s 2008 guidelines for the clinical translation of stem cells point out, human embryonic stem cells and their direct derivatives represent an entirely novel and high-risk product (2008). The same characterization would apply to candidate human induced pluripotent stem cell–derived therapeutics, even more so given the potential problems of using induced pluripotent stem cells as the basis for clinical applications. Complicating the situation, the federal government in the United States, the country that conducts the greatest number of clinical trials, has failed to develop targeted guidelines for trials of pluripotent stem cell therapies. Nor does the U.S. have a national body mandated to provide review and oversight for pluripotent stem cell trials that can offer the kind of constructive guidance the Recombinant DNA Advisory Committee provided during the early years of gene therapy (transfer) research and trials. While, as discussed in Chapter Three, the National Academies of Sciences sponsored an advisory committee that drafted and updated voluntary guidelines for the responsible practice of pluripotent stem cell research from 2005 until 2010, its guidelines offer very little in the way of recommendations for how to conduct clinical trials with pluripotent stem cells. Perhaps it would have developed such guidelines if it had continued its work. The Food and Drug Administration (FDA)’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) did devote a 2008 meeting to discussing clinical trials with therapies developed from human embryonic

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stem cells, but it decided it was then premature to develop guidelines (U.S. Food and Drug 2008). The 2009 National Institute of Health’s Guidelines for Human Stem Cell Research focus on the policies and procedures for eligibility for the federal government’s funding of pluripotent stem cell research and not on broader issues of research and applications (National Institutes of Health 2009). Although the California Institute for Regenerative Medicine (CIRM) has been the most significant sponsor of pluripotent stem cell research and clinical trials, neither the California Department of Public Health Guidelines for Human Stem Cell Research nor CIRM has provided guidance for conducting clinical trials (California Department of Public Health 2018; California Institute for Regenerative Medicine 2017). The 2008, and even more the 2016, editions of the ISSCR’s Guidelines for Stem Cell Science and Clinical Translation provide comprehensive guidelines for clinical trials with pluripotent stem cells, but this document was not issued until after clinical trials had begun, and it lacks official status (International Society for Stem Cell Research 2016). In the U.S., the FDA oversees all clinical trials, including clinical trials with pluripotent stem cell–based therapies. To receive authorization for beginning a clinical trial, the sponsor must submit an Investigational New Drug (IND) application for the FDA to assess whether the product is reasonably safe for testing in humans. The IND application must contain information in three broad areas: animal pharmacology and toxicology studies; information pertaining to the composition, stability, and controls used for manufacturing the investigational product; and detailed protocols for proposed clinical studies, along with information on the qualifications of the clinical investigators (Food and Drug Administration 2008). The FDA reviews data from the Phase I clinical trial before it approves beginning Phase II testing and then repeats the process after Phase II before it consents for the sponsors to proceed to Phase III. However, this process has limitations, as it applies to investigational pluripotent stem cell–based therapies. The FDA does not have specialized guidelines for how it evaluates candidate pluripotent stem cell therapies or a dedicated body with expertise in this area, similar to the UK’s Gene Therapy Advisory Committee, that oversees proposed gene and cell therapy applications. Significantly, the FDA does not evaluate ethical issues in making its decisions. Nor does it have a requirement that sponsors submit an ethical review done by an appropriate ethics committee with its application, as does the UK’s Gene Therapy Advisory Committee. Moreover, the FDA review processes and its decision-making are confidential. This chapter begins by exploring some of the key ethical challenges of conducting FIH trials of pluripotent stem cell–based therapies.

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It then discusses ethical issues that arose in the first clinical trial of a therapy derived from a human embryonic stem cell. The third section identifies the clinical trials of therapies derived from pluripotent stem cells that have been conducted and are underway as of the fall of 2019. It is followed by an analysis of the preliminary outcomes of these early-stage trials. The final section of the chapter reflects on these developments.

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Ethical Challenges of First-in-Human Clinical Trials2 Phase I clinical trials often raise ethical challenges, particularly first-inhuman (FIH) trials. Ethical standards governing clinical research require having a favorable risk-to-benefit ratio and protecting patients from excessive risk. These standards are difficult to achieve in FIH trials, which involve the greatest degree of uncertainty at any point in the drug development process (Kimmelman and London 2011). In contrast with later-stage trials, Phase I trials with novel therapies have little or no human experience on which to draw when conducting a risk-benefit analysis (Kimmelman 2010, 3). Extrapolating from laboratory and animal studies to humans is a complex process under all circumstances, but even more so in proposed FIH trials lacking data from comparator studies in humans to help guide the process. Given the limitations of animal models and the differences between human and animal physiology, toxicological studies in animals may be poor at predicting human outcomes. Additionally, many investigational review boards (IRBs) have difficulty evaluating preclinical data. Instead, they may be inclined to defer to the judgment of the FDA and other regulatory bodies rather than to carefully scrutinize the quality, integrity, and appropriateness of the preclinical models being presented (Kimmelman 2010, 123). Whether trial participants should have a reasonable prospect of benefit has given rise to ethical controversy, especially since the likelihood of any kind of therapeutic benefit in Phase I trials is very slight. Given the emphasis on evaluating toxicity and dosing, some critics have questioned whether Phase I trials can ever be considered to have therapeutic content (King 2000). Regulators and IRBs have usually been willing to go forward with Phase I trials in the absence of likely benefit to participants if the research has the prospect of contributing to generalizable scientific knowledge for social benefit, but the prospect of the trial doing so may also be difficult to assess. Moreover, in such situations, participants bear the risk of harm while society gains the potential benefit. It is unlikely that 2

This section of the chapter draws on my article “Addressing the Ethical Challenges of First-in-Human Trials,” Journal of Clinical Research and Bioethics, 2 (4), 2011).

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participants in a Phase I FIH clinical trial with a therapy derived from pluripotent stem cells will benefit clinically, but, in view of the hype surrounding the development of pluripotent stem cell therapies, many potential participants may assume that that even early stages of the trial will yield a therapeutic benefit. The level of risk to participants in FIH trials often correlates with the innovativeness of the therapy under consideration. The European Medicines Agency (EMEA), the European counterpart to the FDA, has developed guidelines for FIH trials involving potentially high-risk products. It places clinical trials in this category when uncertainty exists regarding (1) the mode of action, (2) the nature of the target, and/or (3) the relevance of animal models, each of which increases the possibility that participants will experience serious harm (Committee for Medicinal Products for Human Use 2007, para. 4.1, p.1). The EMEA guidelines caution that “the higher the potential risk associated with the type of medicinal product and its pharmacological target, the greater the precautionary measures that should be exercised in the design of the first-in-human study” (2007, para 4.4.1, p.9). FIH trials with pluripotent stem cell derivatives qualify under all three of the EMEA’s criteria. Voluntary and informed consent of subjects participating in a scientific study is a central international principle of research ethics related to respect for human persons. Concerns have been expressed, however, about the challenges of obtaining meaningful consent in early-phase clinical trials with pluripotent stem cells. The informed consent process requires that potential subjects be accurately informed of the purpose, methods, risks of adverse events, and the very limited, if any, prospect of therapeutic benefits. It also requires that they understand this information, be able to apply it to their own situation, and make a voluntary and uncoerced decision as to whether to participate in the trial. Each of these components can be especially problematic for FIH trials because there is often no reliable information about benefits and risks for studies of therapeutic agents never before used in humans. Directors of clinical trials and IRBs reviewing and evaluating informed consent documents have the unenviable task of encouraging potential subjects to participate in the trial while dissuading them of the “therapeutic misconception” that confuses scientific research with therapy. Communicating uncertainty and risk and determining whether a patient understands the information is difficult – and made more so because volunteers entering clinical trials often overlook discussions of risk and focus their attention on the possible benefits (Chapman 2011). An additional complicating factor is that early-phase trials involving stem cell–based interventions may enroll research subjects who

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have exhausted standard treatment options and therefore may be prone to overestimating the likelihood of receiving benefit. The International Society for Stem Cell Research (ISSCR) Guidelines recommend that consent procedures in early-phase trials of stem cell–based interventions should therefore work to dispel potential research subjects’ overestimations of the likelihood of receiving a therapeutic benefit and should test the comprehension of prospective subjects about this before accepting their consent (International Society for Stem Cell Research 2016, 22).

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The Historically First-in-Human Clinical Trial of a Human Embryonic Stem Cell Derived Therapy3 In January 2009, the Food and Drug Administration (FDA) approved the Investigational New Drug (IND) application of the Geron Corporation, a small California-based biopharmaceutical company, to initiate a clinical trial to evaluate GRNOPC1, a human embryonic stem cell–derived candidate therapy for severe spinal cord injuries (Geron Corporation 2009). GRNOPIC1, a therapeutic based on human embryonic stem cell–derived oligodendrocyte progenitor cells, was intended to repair recent severe spinal cord injuries. In the absence of an FDA guidance document providing standards for clinical trials with pluripotent stem cell–derived therapies, and given the veil of confidentiality under which IND reviews operate, it is difficult to know the basis on which the FDA made its decision to go forward with this trial. In view of the controversial nature of the field, it is unfortunate that the process could not be more transparent. It is possible that the support the newly elected President Barack Obama had given to human embryonic stem cell research influenced the decision. The Geron protocol for the trial involved the injection of two million cells delivered directly into the lesion site with the goal of inducing tissue repair through the regeneration of damaged neurons. According to Geron, GRNOPC1 stimulated the remyelination of the damaged spinal cord and promoted neuronal survival and activity (Geron Corporation 2009). Geron reported that preclinical studies on rats injected with GRNOPC1 seven days after an injury demonstrated improved locomotor activity. Also, histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons (Geron Corporation 2010c). 3

Parts of this section are derived from my previously published article with Courtney C. Scala, “Evaluating the First-in-Human Clinical Trial of a Human Embryonic Stem Cell Based Therapy,” Kennedy Institute of Ethics Journal (2012).

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In May 2009, before the clinical trial had begun, the FDA issued a hold, possibly because additional animal data Geron had submitted after approval indicated that rats with severed spinal cords receiving the GRNOPC1 treatment developed a higher frequency of cyst formation at the injury site than had been observed in previous animal studies done with less severely injured rats. After Geron conducted additional preclinical animal studies, the FDA lifted its clinical hold, thus enabling Geron to proceed with its clinical trial of GRNOPC1. The design of the Phase 1 single-dose, openlabel, multi-center trial was to enroll eight to ten patients at up to seven medical centers selected by Geron. The goal was to assess the safety and tolerability of GRNOPC1 in patients with acute thoracic spinal cord injuries (Geron Corporation 2010b). Geron also announced that the evaluation of efficacy, such as improved neuromuscular control of sensation in the trunk or lower extremities, constituted a secondary end. To be eligible, potential participants in the study were required to have documented evidence of a functionally complete spinal cord injury resulting in paralysis and to agree to have GRNOPC1 injected into the lesion sites between seven and fourteen days after the injury. The first patient in the clinical trial was treated on October 11, 2010. Altogether, five participants were injected, apparently without suffering serious adverse effects or evidence of immune rejection of GRNOPC1, including after withdrawal of the immunosuppressive drug. One patient experienced two mild adverse events associated with the immune-suppressive drug. However, none of the subjects showed any improvement in their conditions (Geron Corporation 2011a). Unexpectedly, in November 2011, Geron announced it was halting the trial and withdrawing from the stem cell field. In a statement, the company claimed its decision was motivated by capital scarcity and uncertain economic conditions, not the lack of promise of stem cell therapies. The company said that it would monitor the patients already in the trial and that it was looking for partners with the technical and financial resources to continue the trial and advance its stem cell programs (Geron Corporation 2011b). Eventually, Geron transferred its stem cell assets to Asteria Biotherapeutics, a subsidiary of Biotime. Asterias was eventually able to obtain FDA approval for a Phase 1/2a trial with an expanded application of what was now labeled AST-OPC1 for a wider range of severe spinal cord injuries and with somewhat longer eligibility from the date of the injury than Geron’s two weeks limitation. By 2018, Asterias had injected without problems 25 patients with a positive safety profile and signs of cell engraftment at the injury site (Asterias Biotherapeutics 2018).

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It is helpful to take the Geron clinical trial as a case study in how to assess the ethical and scientific prerequisites to warrant exposing human subjects to the risk of testing pluripotent stem cell–based therapies. Selection of appropriate animal models with similarities to human biological responses is a critical element of assuring adequate preclinical evidence. Inappropriate animal models may fail to predict human risks and thereby fail to prevent adverse effects in clinical trials. Conversely, such models may predict clinical benefits that fail to materialize in humans (Dresser 2009). Therefore, it would seem an appropriate precaution to test any proposed pluripotent stem cell–based therapeutic on a variety of animal models before beginning human trials. The International Society for Stem Cell Research (ISSCR) guidelines recommend that investigators should develop preclinical cell therapy protocols in both small and large animal models when deemed necessary by independent peer review or regulatory review (International Society for Stem Cell Research 2008, recommendation 8). Members of the spinal cord injury research community also recommended demonstration of efficacy in large animal models and independent replication of promising results before clinical testing spinal cord therapies (Kwon, Hillyer, and Tetzlaff 2010). Geron submitted an IND application to the FDA claiming evidence of the safety, tolerability, and efficacy of GRNOPC1 from twenty-four separate animal studies, but all of these data were from research conducted with rodents. Geron did not test GRNOPC1 on any larger mammals. It is important to build safety measures into a first-in-human (FIH) trial design, especially when the testing involves a high-risk and completely novel agent. The ISSCR guidelines underscore the importance of having persuasive preclinical evidence of safety and benefit to justify proceeding to clinical trials in humans. The guidelines also address the need to identify and reduce the risks of stem cell–based interventions, including cell proliferation, tumor development, and exposure to animal source material (International Society for Stem Cell Research 2008, recommendation 24). Here, it is relevant to note that the Geron trial involved implantation of cells into the spinal cord. The CTGTAC briefing document noted that “undesirable proliferation or differentiation that occurs in some anatomical sites may be more deleterious than for others; for example spinal cord or brain vs. peritoneal cavity” (Food and Drug Administration 2008, 6). Geron assumed that the implantation of its cells would be localized and would not proliferate into other areas (Geron Corporation 2009), but what had transpired in the rodent experiments would not necessarily carry over into human subjects. Fortunately, there were no proliferation problems.

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Given the novelty of cell-based products and the new and potentially unknown challenges in their processing and manufacture, the ISSCR guidelines emphasize the need for the processing and manufacture of any cell-based product to be conducted under scrupulous expert and independent review and oversight in order to ensure their quality and safety to the greatest extent possible (International Society for Stem Cell Research 2008, sec. 4). While the guidelines do not completely rule out the inclusion of animal materials in the cell manufacturing process, ISSCR underscores that doing so raises unique concerns that must be addressed by additional testing to minimize the risk of transmission of animal pathogens and reaction to animal proteins (International Society for Stem Cell Research 2008, sec. 4.1.2). ISSCR also recommends that, where possible, components of animal origin used in the culture or preservation of cells be replaced with human components in order to reduce the risk of accidental transfer to patients of unwanted biological material or pathogens (International Society for Stem Cell Research 2008, recommendation 6). The quality standards and safety of the product Geron used in its clinical trial conformed to some, but not all of the ISSCR guidelines. According to information provided by Geron, GRNOPC1 was produced using Good Manufacturing Practices in its manufacturing facilities, and its GRNOPC1 production process and clean-room suites were inspected and licensed by the state of California (Geron Corporation 2009). However, there was a problem with the source of the cells. The company developed its oligodendrocyte progenitor cells from one of the original human embryonic stem cell lines, created in 1998 at the University of Wisconsin, Madison. All of the early human embryonic stem cell lines, including the ones that Geron used to develop GRNOPC 1, had been nurtured on mouse feeder layers. It was only several years later that scientists developed a method for culturing human embryonic stem cells without the contamination of an animal feeder layer. Like other xenotransplants, Geron’s therapeutic therefore had the potential to convey exposure to unknown animal viruses. Geron claimed to have purified the cells, but there are no comprehensive screens for murine viruses. Much as with gene therapy and cancer trials, pluripotent stem cell trial participants are likely to be patients suffering from the medical problem the therapy is designed to address rather than healthy volunteers. Seriously ill patients are more vulnerable subjects because their underlying medical disabilities increase their susceptibility to conflate research trials designed to produce scientific data with access to therapy. Research has shown that such subjects in clinical trials frequently overestimate the likely benefits of participation in research studies, underestimate the risks involved, and

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generally conflate research with ordinary treatment (Lidz et al. 2004). Many subjects in early-phase gene therapy trials apparently assumed they would receive a therapeutic benefit, in part because consent documents were inappropriately optimistic about the potential benefits of trial participation (Kimmelman and Palmour 2005; King et al. 2005). This failure to appreciate the difference between research and therapy, termed the therapeutic misconception, significantly affects participants’ assessment of risk. By doing so, it poses a serious problem for the ethical conduct of clinical trials of novel therapies. Participants in pluripotent stem cell clinical trials may be particularly susceptible to the therapeutic misconception because this research has received sustained media and industry buildup regarding its capacity to provide treatment and cures for a variety of currently untreatable disorders (Cho and Magnus 2007). Publicity has acclaimed research advances in the field, often without appropriate qualifications. The Geron Corporation promoted unrealistic hopes for clinical benefit in its trial, proposing in its statements the possibility that subjects might experience some improvement in their range of motion (Geron Corporation 2010a). Obtaining meaningful informed consent can be particularly challenging for clinical trials involving highly innovative therapies. The ISSCR guidelines underscore the importance of ensuring subject comprehension and propose several additional safeguards. Patients need to be informed when novel stem cell–derived products have never been tested before in humans. They should be told that researchers do not know whether the therapy will work as hoped. They should also be advised of the possibility that cell-based interventions may generate adverse effects lasting for their entire lifetime (International Society for Stem Cell Research 2008, recommendation 28; 2016, recommendation 3.3.2.6). To qualify for participation in the Geron trial, patients had to have suffered a traumatic and life-changing severe spinal cord injury less than two weeks before their enrollment. The potential subjects might have been legally competent, but they were likely to have been a vulnerable population in shock, depressed, and compromised in their ability to understand and weigh the risks and benefits of participating in a trial of a complex, potentially risky, and untested technology (Scott 2008). Newly disabled people may also underestimate the degree to which the emotional impact of their injury compromises their judgment. They may also be more inclined to agree to participate in a trial in the initial days after their injury, no matter how remote the possibility of an improvement in their quality of life, than after they have adjusted to life in a wheelchair (Scott 2008). It has been suggested that other populations would provide a better target population

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for a safety trial, specifically chronic complete spinal cord injury patients (Bretzner et al. 2011). Given all of the ethical issues with the Geron clinical trial, it would have been preferable for the FDA to have waited to authorize its initial FIH trial of an embryonic stem cell–derived therapeutic, especially since there had been a more appropriate candidate available. In 2010, the FDA authorized Advanced Cell Technology’s Investigational New Drug application to initiate a Phase I/II multicenter study using retinal cells derived from human embryonic stem cells to treat patients with Stargardt’s disease. In early 2011, Advanced Cell Technology (renamed Ocata Therapy and then Astellas Pharma) received FDA clearance for a second clinical trial, this one using their embryonic stem cell–based therapy to treat dry agerelated macular degeneration (Advanced Cell Technology 2011). Diseases affecting the eye are attractive FIH applications because the eye constitutes an accessible and relatively immunoprivileged site, due to its ability to tolerate foreign antigens or non-histocompatible cells without eliciting an immune response. Also, the subretinal space in the eye is protected by the blood–ocular barrier (Schwartz et al. 2012). Another advantage is that Advanced Cell Technology had developed a method to generate embryonic stem cell lines without requiring embryo destruction by removing single blastomeres from an embryo using a technique similar to preimplantation genetic diagnosis (Chung et al. 2008).

Other Clinical Trials Conducted with Therapies Derived from Pluripotent Stem Cells Clinical trials typically have three phases. After receiving approval from the FDA – or, if conducted elsewhere, a regulatory body in that country – clinical trials begin with Phase I, which usually describes a trial involving a small number of participants designed to determine the safety of the therapy and its maximum tolerable dose. Phase I studies are not usually designed to assess efficacy, and the agent is usually given at a sub-therapeutic level unlikely to produce a therapeutic benefit. After receiving authorization from the appropriate regulatory agency based on its review of data from Phase I, trial sponsors can begin Phase II trials, which are conducted with larger numbers of participants than Phase I trials. Phase II studies also assess efficacy – that is, whether the intervention under investigation has or might have the desired clinical effect on the targeted condition. In contrast, Phase III studies, which also require authorization, this time based on review of data from Phase II, are usually randomized clinical trials conducted with much larger numbers of participants and designed to assess efficacy. In

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Phase III trials, participants are typically placed into different groups in a random way, some of which are given the investigational therapy and others the current standard of care or, if there is none, a placebo. However, it is likely that most Phase III trials with pluripotent stem cell–based therapies will be non-randomized and that all of their participants will receive the investigational therapy. In the United States, estimates are that less than 20 percent of therapies put through Phase I clinical trials make it through Phase III successfully and receive FDA approval for clinical use (Magnus 2010). Most of the trials with pluripotent stem cell–derived therapeutics conducted to date are Phase I or Phase I/II studies. At the time of writing, a few embryonic stem cell–derived therapies have begun Phase II initial efficacy trials, but none are reported as proceeding to Phase III trials as yet. Table 6-1 lists the trials of human embryonic stem cell–based therapeutics completed or in process as of July 2019. The trials are taking place in a variety of countries: France, the United States, the UK, Israel, Korea, various locations in China, and Brazil. The largest number of trials are in the United States. The multiple listings for some sponsors with trials for the same disorder reflect different study ID numbers in the clinical trials database, usually because of changes in the trial protocol. In a few cases, the sponsor changed its name or sold its investigational work and intellectual property to another entity which has continued the project under another name after receiving regulatory approval to do so. Table 6-2 lists the trials of human induced pluripotent stem cell– derived therapies. There are fewer such trials in process than of human embryonic stem cell–based therapies. Several sponsors have announced they will shortly begin trials with induced pluripotent stem cell–based products, so there are likely to be more such trials in the near future. As noted, most of the trials using induced pluripotent stem cell–derived therapeutics have taken place in Japan, reflecting the government’s promotion of and support for the development of therapies using these cells.

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Table 6-1. Clinical Trials with Human Embryonic Stem Cell–Based Therapies Sponsor Assistance Publique-Hopitaux de Paris Assistance Publique-Hopitaux de Paris Astellas Pharma Astellas Pharma Astellas Pharma Astellas Pharma Astellas Pharma Astellas Pharma Astellas Pharma Asterias Biotherapeutics Asterias Biotherapeutics Cell Cure Neurosciences CHA Biotech CHA Biotech Chinese Academy of Sciences Chinese Academy of Science Chinese Academy of Science Chinese Academy of Science Institute of Zoology Eye Institute of Xiamen University Federal University of Sao Paolo Geron Corporation International Stem Cell Corp. London project to Cure Blindness Ocata Ocata Ocata Pfizer Pfizer Regenerative Patch Technologies Southwest Hospital, China Viacyte Viacyte Viacyte Viacyte

Disease Ischemic heart disease

Location France

Parkinson’s disease*

France

Stargardt macular dystrophy Advanced dry AMD AMD AMD Stargardt macular dystrophy Stargardt macular dystrophy Macular degenerative disease Spinal cord injury Spinal cord injury AMD Dry AMD Stargardt macular dystrophy Dry AMD Nonexudative AMD Parkinson’s disease Retinitis pigmentosa Dry AMD Severe ocular surface diseases AMD, Stargardt disease Spinal cord injury Parkinson’s disease* Wet macular degeneration retina Geographic atrophy secondary to macular degeneration Stargardt macular degeneration Dry macular degeneration AMD AMD Dry AMD Macular degenerative disease Diabetes mellitus type 1 Diabetes mellitus type 1 Diabetes mellitus type 1 Diabetes mellitus type 1 with hypoglycemia

United States United States Not specified Not specified UK United States Not specified United States United States Israel & U.S. Korea Korea China China China China China China Brazil United States Australia UK United States United States United States UK UK United States China Canada U.S., Canada U.S., Canada United States

Notes: AMD is age-related macular degeneration. * using neural cells derived from human parthenogenetic stem cells Sources: Guhr et al. (2018), 15; Ilic et al. (2015), 20; Trounson and McDonald (2015), 12.

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Table 6-2. Clinical Trials with Induced Pluripotent Stem Cell–Based Therapies Sponsor Riken Cynata Therapeutics Kobe City Med Center General Hospital Kyoto University Keio University School of Medicine Osaka University Fate Therapeutics

Disease Exudative AMD** Graft-versus-host disease Neovascular AMD* Parkinson’s disease** Spinal cord injuries** Heart disease* Cancer treatment**

Location Japan Australia, UK Japan Japan Japan Japan U.S.

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Notes: * based on allogenic induced pluripotent stem cells ** based on autologous induced pluripotent stem cells Source: Guhr et al. (2018), 493; Zimmer (2018); RegMedNet (2018); Normile (2018); Galindo (2019).

As indicated in the tables, much of the focus of the initial pluripotent stem cell clinical trials has been on ophthalmic indications. As noted above, the eye constitutes an accessible and relatively immuneprivileged site. That means it has an ability to tolerate foreign antigens or non-histocompatible cells without eliciting an immune response. Also, the subretinal space in the eye is protected by the blood–ocular barrier (Schwartz et al. 2012). In addition, the eye is accessible for injection or surgery, and it can be noninvasively monitored by visualization through a lens after injection of the therapy (Kimbrel and Lanza 2015). Advanced Cell Technology, which became Ocata Therapy and then was sold to Astellas Pharma, has, in early clinical trials, implanted patients with advanced stage Stargardt’s macular dystrophy and dry agerelated macular degeneration using retinal pigment epithelium cells derived from embryonic stem cells. The Chinese Academy of Sciences has also conducted clinical trials with a product derived from human embryonic stem cells for age-related macular degeneration and retinitis pigmentosa. Pfizer Corporation, London is conducting trials for macular degeneration using a human embryonic stem cell–derived therapeutic, as is Southwest Hospital in Chongquing, China. The Federal University of São Paulo in Brazil has undertaken clinical trials for two forms of advanced macular degeneration and Stargardt disease. CHA Biotech in Seoul, Korea is yet another sponsor of clinical trials with a therapy derived from human embryonic stem cells for macular degeneration and Stargardt macular dystrophy. In addition, Cell Cure Neurosciences, a subsidiary of BioTime, is testing its therapy derived from human embryonic stem cells for advanced macular degeneration. The Eye Institute of Xiamen University in Fujian, China has a clinical trial for severe ocular surface diseases.

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There have also been two clinical trials with induced pluripotent stem cell–derived therapies for eye disorders. Riken, a large scientific institute in Japan located just outside of Tokyo, is conducting a trial for exudative (wet) age-related macular disorder. The General Hospital at the Kobe City Medical Center in Japan has a trial for neovascular age related macular degeneration, a form of wet macular degeneration. NIH has announced it also plans to begin a clinical trial using a therapeutic based on human induced pluripotent stem cells for macular degeneration (Begley 2019). Stargardt’s macular dystrophy is a genetic eye disorder that appears in late childhood or early adulthood and worsens over time leading to central vision loss. It affects one in 10,000 people (National Eye Institute, n.d.). Age-related macular degeneration is a degenerative retinal disease that can cause severe, irreversible vision loss in people over the age of 50. It is a leading cause of blindness among people older than 50 years, affecting about 11 million people in the U.S. (National Eye Institute, n.d.). Retinitis pigmentosa is a group of rare, genetic eye disorders that involve a breakdown and loss of cells in the retina that causes a loss of peripheral vision and difficulty seeing at night (Boyd 2019). The ocular surface refers to the cornea and disorders of the cornea can affect vision and produce discomfort or pain (Bascom Palmer Eye Institute, n.d.). Currently there are no approved effective therapies for macular degeneration, Stargardt’s macular dystrophy, or retinitis pigmentosa. There are also several clinical trials in process or planned for neurological disorders. Geron’s short-lived trial testing human embryonic stem cell–derived oligodendrocytes for spinal cord injury was taken over by Asterias Biotherapeutics using Geron’s cells under a rebranded name. Keio University School of Medicine in Japan is also beginning a clinical trial using induced pluripotent stem cells for spinal cord injury. The Chinese Academy of Science, in collaboration with the First Affiliated Hospital of Zhengzhou University and the International Stem Cell Corporation (Australia), is currently testing neural progenitor cell–based therapies for Parkinson’s disease, the second most common neurological disorder. The former is using a human embryonic stem cell–based therapy and the latter a human parthenote–based therapy. Kyoto University is currently testing an induced pluripotent stem cell–based therapy for Parkinson’s disease. Several other studies testing pluripotent stem cell–based therapies for Parkinson’s disease are in process or in the offing. International Stem Cell Corporation is conducting a clinical trial with parthenogenic stem cell– derived neural cells intracranially transplanted into patients with moderate Parkinson’s disease. Parkinson’s Disease is a neurogenerative disorder

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affecting movement. Some 60,000 Americans are diagnosed with Parkinson’s Disease each year and about 10 million people worldwide are living with the disease. Medication can initially control some of the symptoms but becomes progressively ineffective (Parkinson’s Foundation n.d.). Parkinson’s is particularly amenable to cell replacement therapy, as the injection of cells can be targeted to the small, defined region of the midbrain where dopaminergic neuron degeneration occurs (Kimbrel and Lanza 2015, 685). Viacyte Corporation has launched trials to test its therapy for type 1 diabetes in several locations. Their encapsulated pancreatic progenitor cells, derived from human embryonic stem cells, are designed to replace lost insulin-producing beta cells and restore glucose control (ViaCyte Corporation 2018). Fate Therapeutics is conducting a cancer trial using a clonal master induced pluripotent stem cell line as a renewable cell source. Their therapy is intended to be an option for cancer and immune system disorders (Fate Therapeutics 2019).

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Preliminary Outcomes of Clinical Trials with Investigative Pluripotent Stem Cell–Based Therapies In evaluating the outcomes of the clinical trials to date, it is important to remember that Phase I clinical trials typically involve a small number of subjects and are designed to assess safety and appropriate dosage levels and are not intended to have therapeutic benefits. Participants are usually given what is assumed will be a sub-therapeutic dosage of the investigational product. Nevertheless, a few of the sponsors of pluripotent stem cell trials describe their trials as both safety and preliminary efficacy studies, possibly to attract participants and investors (International Stem Cell Corporation, n.d.). The numbers of subjects in these trials can be as limited as the six in the trial of the Hôpitaux de Paris’ transplantation of human embryonic stem cell–derived cardiovascular progenitors for severe ischemic left ventricular dysfunction (Miller 2018). In some it can be up to the 25 in Asterias’ trial of a human embryonic stem cell–derived oligodendrocyte spinal cord candidate therapy or the plan to involve 69 subjects in the Viacyte trial of a human embryonic stem cell–derived endocrine islet cells for diabetes mellitus (California Institute for Regenerative Medicine, n.d.). The small numbers involved usually limit statistical power. Another limitation is that only a few of the early trials have a control group for comparison. Nor has there been adequate time to track the long-term impact on participants. There is no documentation that any of the patients in the studies using human embryonic stem cell–based therapies have suffered adverse

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effects from the implanted cells. None of the trials have reported problems with rejection of the transplanted cells, uncontrolled stem cell proliferation, ectopic tissue formation, or other serious safety issues, including the invasive trials such as the Parkinson’s disease clinical trial, which injected cells into the brain. Most of the trials have used short-term immune suppressants as precautions, which participants have tolerated. The subjects involved in the original Geron trial for thoracic spinal injury were followed for seven years without any identified adverse effects associated with the cells or with the immunosuppressive regime. Immune monitoring of subjects for one year post-transplantation showed no evidence of cellular immune responses, despite complete withdrawal of all immunosuppression at sixty days post-transplantation. Nor did the subsequent 25 subjects have any unexpected adverse events (Asterias 2018). There were some surgical complications in Advanced Cell Technology’s trials, consistent with the risks associated with surgery for macular disorders. A few participants also developed visually significant progression of cataracts. Two patients, one with age-related macular degeneration and one with Stargardt’s macular dystrophy, required cataract surgery six to 12 months after implantation, and two other patients with Stargardt’s macular dystrophy underwent elective surgery after the first year. One subject developed an infection (Schwartz et al. 2015, 514). However, no patients showed signs of rejecting the implant. There were reported problems with patients in the Hôpitaux de Paris cardiovascular trial, but the two deaths that occurred were both attributed to the patients’ underlying conditions and not the transplanted stem cell–derived cardiovascular progenitors. The five patients selected for the trial had a median age of 66.5 years and all had severe ischemic left ventricular dysfunction. One patient died early post-operatively from treatment-unrelated comorbidities. All of the others were reported to have had uneventful recoveries and to be symptomatically improved. Then, another patient died from heart failure 22 months after the trial (Menasché et al. 2018). Again, this was likely a result of their underlying condition. There have been some safety issues and problems with induced pluripotent stem cell–based therapies that derive directly from the cells. In 2014, the Riken Center for Developmental Biology conducted a trial for macular degeneration using an autologous transplant of retinal pigment epithelium cells generated from induced pluripotent stem cells. As noted in Chapter Two, the first patient in this trial did not suffer any serious adverse effects, but the safety testing of the second patient’s induced pluripotent stem cells revealed several mutations in the genetic sequence that did not exist in the patient’s original fibroblasts. Problematically, one of the single-

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nucleotide variations was identified as a cancer-associated mutation (Blair and Barker 2016, 423). The investigators at Riken decided to change strategy by using partially matched allogeneic cells instead of the patient’s own cells (Garber 2015, 891). When five patients were then treated for the same eye condition with induced pluripotent stem cell–derived retinal cells developed from different donors, one of them developed a serious, but not life-threatening, reaction to the transplant, requiring doctors to remove it (Zimmer 2018). There have been some promising results, particularly from the trials for eye disorders, even though Phase I trials are designed to be safety trials. In Advanced Cell Techology/Ocata’s two trials of human embryonic stem cell–derived retinal pigment epithelium cells, improvements in visual acuity occurred in more than half of the eyes treated. In terms of letters on the eye chart, visual acuity improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye. Eight of 18 patients had an improvement in visual acuity of at least 15 letters during the first year after surgery, which corresponds to a doubling of the visual angle, something that is generally accepted to be a clinically significant measure of improvement. Participants in the studies also reported improvement in their general vision and peripheral vision. There was a lack of improvement in subjects’ other untreated eyes, which served as controls (Schwartz et al. 2015). In other human embryonic stem cell trials, Asterias Biotherapeutics reported that magnetic resonance imaging has shown that its AST-OPC1 cells have engrafted at the injury site. Also, nine of the 12 subjects in the two cohorts that received the largest infusions of cells in its testing of escalating dosages have improved upper extremity motor function by two motor levels (Asterias 2018). The two-year data from cohort one of ViaCyte’s trial of its encapsulated candidate pancreatic progenitor cells showed that, when engraftment did occur, viable mature insulin-expressing endocrine islet cells were formed and in some cases persisted for up to two years after implantation, the longest time point investigated in the study (ViaCyte Corporation 2018).

Reflections The interest in pluripotent stem cell research and the investment of public funds have given rise to questions and criticism as to why the field is not developing therapies more quickly. Are these questions and criticism fair? At the time of writing, some 40 clinical trials are taking place, mostly in the early stages of clinical testing, but no pluripotent stem cell–based therapies have as yet been approved for clinical practice by the U.S. Food and Drug

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Administration (FDA) or an equivalent regulatory body in another country after undergoing the full sequence of clinical testing. Japan, which has created a conditional approval scheme for regenerative medicine products, has accorded three regenerative medicine products, at least one of which is a stem cell treatment product, conditional approval based on preliminary evidence (Sietsema et al. 2018). But, in assessing this progress, it is important to take into account that it has only been some 20 years since the first derivation of human embryonic stem cells and 12 since the discovery of human induced stem cells. It should be remembered that it took more than 30 years from the beginning of clinical trials for the first gene therapy to receive approval. In the past two decades, the pluripotent stem cell field has progressed from initial discovery to a vibrant research field to clinical trials for several different types of disorders. Currently far more clinical trials are being conducted with human embryonic stem cell derivatives than with human induced pluripotent stem cell–based therapies. The good news is that the trials with human embryonic stem cell–based therapies have gone well. No significant adverse events have been reported. The number of trials for ophthalmic disorders and the initial promising results in some of them suggest that these investigational therapies will be the first ones to receive regulatory approval to proceed to market. There are, however, some potential problems on the horizon. As noted in Chapter Four, Phase III trials are very expensive, and the sponsors of the investigational therapies with pluripotent stem cells are mostly small biotechnology firms and academic centers, neither of which is likely to have access to the resources needed to conduct Phase III trials. Also, as the clinical trials are proceeding, some of the existing sources of funds for the field may be drying up. Importantly, CIRM, which has been the spark plug for stem cell research and clinical trials, has spent its $3 billion and at this time it is uncertain whether the voters in California will agree to provide a second installment of $5 billion that will enable it to continue its support for clinical trials. In contrast, the enthusiastic support of the Japanese government for investigational therapies based on human induced pluripotent stem cells places the development of these clinical applications on a stronger financial foundation, and more of these therapies may be made available to patients in the near future. But this scenario has worrisome aspects. At this point in time, the issues with human induced pluripotent stem cells raised in Chapter Two have not be resolved. Hence there are still significant questions about the appropriateness of using induced pluripotent stem cells as the basis for clinical applications. As noted, there were problems in some of the initial trials of candidate therapies based on induced

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pluripotent stem cells. Given this situation, Japan’s 2014 law designed to accelerate the approval of regenerative medicine applications, combined with its commitment to promote induced pluripotent stem cell therapies, raises additional concerns. As discussed in Chapter Three, under this framework, a product can be approved based on preliminary data from small patient cohorts with predicted, but not proven, indications of efficacy. Pivotal confirmatory trials can take place after the product becomes available to patients in Japan. This means that a conditional marketing authorization may be granted without the need for Phase III clinical trials. This is a risky path where one serious setback could have repercussions for the entire field.

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Progenitors for Severe Ischemic Left Ventricular Dysfunction.” Journal of the American College of Cardiology 71 (4): 429–38. Miller, Leslie W. (2018) “Trial of Embryonic Stem Cell–Derived Cardiac Progenitor Cells: An Encouraging Start.” Journal of the American College of Cardiology 71 (4): 439–42. National Eye Institute (n.d.) “Age-Related Macular Degeneration (AMD) Data and Statistics.” National Eye Institute (Accessed 23 May 2020). https://www.nei.nih.gov/learn-about-eye-health/resources-for-healtheducators/eye-health-data-and-statistics/age-related-maculardegeneration-amd-data-and-statistics. National Eye Institute (n.d.) “Stargardt Disease.” National Eye Institute (Accessed 23 May 2020). https://www.nei.nih.gov/learn-about-eyehealth/eye-conditions-and-diseases/stargardt-disease. 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. Normile, Dennis (2018) “First-of-Its-Kind Clinical Trial Will Use Reprogrammed Adult Stem Cells to Treat Parkinson’s.” Science, July. https://www.sciencemag.org/news/2018/07/first-its-kind-clinical-trialwill-use-reprogrammed-adult-stem-cells-treat-parkinson-s. RegMedNet (2018) “Preparing for First Human Trial of iPSC-Derived Cells for Parkinson’s Disease: An Interview with Jun Takahashi.” RegMedNet (Accessed 23 May 2020). https://www.regmednet.com/users/3641-regmednet/posts/38627preparing-for-first-human-trial-of-ipsc-derived-cells-for-parkinson-sdisease-an-interview-with-jun-takahashi. Schwartz, Steven D., Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K. Pan, Rosaleen M. Ostrick, Edmund Mickunas, Roger Gay, Irina Klimanskaya, and Robert Lanza (2012) “Embryonic Stem Cell Trials for Macular Degeneration: A Preliminary Report.” The Lancet 379 (9817): 713–20. Schwartz, Steven D., Carl D. Regillo, Byron L. Lam, Dean Eliott, Philip J. Rosenfeld, Ninel Z. Gregori, Jean-Pierre Hubschman, et al. (2015) “Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium in Patients with Age-Related Macular Degeneration and Stargardt’s Macular Dystrophy: Follow-up of Two Open-Label Phase 1/2 Studies.” The Lancet 385 (9967): 509–16. Scott, Christopher (2008) “What Stem Cell Therapy Can Learn from Gene Therapy.” Nature Reports Stem Cells, September. https://doi.org/10.1038/stemcells.2008.123.

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Sietsema, William K., Yoshiyuki Takahashi, Kosuke Ando, Tetsuro Seki, Atsuhiko Kawamoto, and Douglas W. Losordo (2018) “Japan’s Conditional Approval Pathway for Regenerative Medicines.” Regulatory Focus, May. Trounson, Alan, and Courtney McDonald (2015) “Stem Cell Therapies in Clinical Trials: Progress and Challenges.” Cell Stem Cell 17 (1): 11–22. ViaCyte Corporation (2018) “Two-Year Data from ViaCyte’s STEP ONE Clinical Trial Presented at ADA 2018.” Press release (Accessed 23 May 2020). https://viacyte.com/press-releases/two-year-data-from-viacytesstep-one-clinical-trial-presented-at-ada-2018/. Zimmer, Katarina (2018) “First iPS Cell Trial for Heart Disease Raises Excitement, Concern.” The Scientist, August. https://www.the-scientist. com/news-opinion/first-ips-cell-trial-for-heart-disease-raisesexcitement--concern-64743.

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CHAPTER SEVEN

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DEVELOPING GAMETES FROM PLURIPOTENT STEM CELL LINES: A NEW PATH TO REPRODUCTION?

Not all potential applications of pluripotent stem cells are ethical or appropriate to pursue. To date, much of the focus of pluripotent stem cell research has been on the eventual development of therapies. There are other potential applications. Chapter Two discusses the role of pluripotent stem cells, particularly induced pluripotent stem cells, in disease modelling and drug discovery. Scientists have also bioengineered blood stem cells into a delivery vehicle for a cancer treatment molecule that enables them to enter the bone marrow to treat acute myeloid leukemia (McCormack 2018). In addition, researchers have discovered that, when human pluripotent stem cells are placed in three-dimensional culture systems, they can undergo selfassembly and morphogenesis to develop into miniature organoid structures that resemble the anatomy and physiology of intact organs. For example, scientists have created brain organoids, which are miniature threedimensional human brains grown in the laboratory, from stem cells, including a nearly complete mini-brain with an identifiable structure, equal in maturity to the brain of a five-week-old fetus (Ohio State University 2015). The potential benefits of this research include helping to illuminate early brain development and providing better understandings of neurodevelopmental disorders such as autism, Alzheimer’s disease, and schizophrenia. Other research teams have observed that, under certain conditions, human pluripotent stem cells can self-organize in vitro into structures that resemble early embryos able to recapitulate key developmental features of gastrulation (Munsie, Hyun, and Sugarman 2017). Translating pluripotent stem cells into treatment applications for diseases has usually not been controversial, at least for persons supporting human embryonic stem cell research, provided the research has followed ethical and scientific guidelines and regulations. Some commentators have even speculated that the discovery of treatments through applications of

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human embryonic stem cells will eliminate or at least significantly reduce the ethical controversy surrounding them. This hypothesized acceptability is not the case, however, with the possible use of pluripotent stem cells for reproductive purposes. The ability of pluripotent stem cells to develop into any of the cells in the human body has meant that it was only a matter of time before scientists would at least try to transform them into human gametes. These germline cells can be considered the ultimate stem cells. Progress has already been made toward producing what have variously been termed stem cell–derived gametes or artificial gametes through what has been called in vitro gametogenesis, although there is still much that is unknown. A recent book even contemplates that in twenty to forty years most people in developed countries will cease reproduction through sex and instead will rely on pluripotent stem cell–derived gametes, most likely developed from induced pluripotent stem cells (Greely 2016). The development of human gametes from pluripotent stem cells would be a valuable resource for fertility research, and the knowledge gained would likely contribute to the clinical treatment of infertility. Stem cell–derived gametes might also offer the possibility of enabling couples with fertility problems, individuals without suitable gametes, same-sex couples, and fertile couples with a high risk of passing serious diseases on to their progeny to have genetically related children. However, the use of pluripotent stem cell–derived gametes for reproductive purposes would present significant safety, ethical, and regulatory challenges. It is important to evaluate these issues before the science proceeds any further. This chapter will explore these issues. It first provides an overview of the state of the scientific research in this field and the prospects for developing human gametes and embryos from pluripotent stem cell lines. It then identifies the potential beneficial applications the development of human gametes from pluripotent stem cells could have. It next considers whether and how it would be possible to determine the safety of using pluripotent stem cell–derived gametes for reproductive purposes. The chapter then goes on to discuss the ethical issues involved in using pluripotent stem cell–derived gametes as background to framing recommendations about the translation of stem cells into gametes and their application to reproductive purposes.

Current State of the Science Scientists are exploring several pathways in their attempts to create human gametes from pluripotent stem cells. A 2015 review article identified eight

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biologically plausible approaches towards the development of artificial sperm in males and nine potential routes leading to the production of stem cell–derived ooctytes in females. The article also discussed a variety of biologically plausible routes that could lead to the development of stem cell–derived ooctyes in males and nine biologically plausible routes that could result in the development of stem cell–derived sperm in females (Hendriks et al. 2015). However the development of cross-sex stem cell– derived gametes is considered to be far more difficult to achieve, particularly the derivation of sperm from female stem cells because factors on the Y chromosome needed for spermatogenesis would not be present (Human Fertilisation & Embryology Authority 2009, 3). The authors acknowledged that the state of knowledge concerning the functionality and safety of stem cell–created gametes using any of these methods was still preliminary (Hendriks et al. 2015). The situation has not changed significantly since then. While published research has documented some promise with the development of human gametes from pluripotent stem cells, many technical hurdles remain. Several papers have described the successful in vitro development of primordial germ cells in mice from mouse embryonic stem cells. One group injected mouse sperm cells derived from embryonic stem cells into unfertilized mouse eggs, resulting in the birth of offspring, but the pups were abnormal, most likely due to defective imprinting, and died shortly after birth (Nayernia et al. 2006). A few years later, researchers in Japan induced mouse stem cells into becoming functional sperm and oocytes, and then used the gametes to produce healthy mouse pups that went on to be fertile themselves (Katsnelson 2012). A 2015 assessment of biological progress in mice indicated that live births of apparently healthy offspring had already been achieved using gametes derived both from embryonic stem cells and from induced pluripotent stem cells. However, few of these studies had assessed safety in terms of the genetic and epigenetic normality of the artificial gametes or the epigenetic status or long-term health status of the offspring derived from them (Hendriks et al. 2015, 292). Moreover, many of the findings that were reported have yet to be validated by other research groups repeating the experiments. In evaluating progress in the development of stem cell–derived gametes, it is also important to note that differences between human and mouse stem cells mean that advances in murine research do not translate directly into human applications. Mouse embryonic stem cells are “naïve,” which means they are easy to coax into differentiation paths, whereas human stem cells are “primed” in a way that makes them less adoptable (Cyranoski 2014). Also, the reproductive process of mice differs from that

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of humans in key ways and their life spans are very short. Scientists have not yet developed and implanted into large mammals artificial gametes that would provide better models for human reproduction. Nor has there been research verifying stability and safety over multiple generations, even in mice. There have been initial steps with the development of human stem cell–derived gametes, both using human embryonic stem cells (National Institutes of Health 2009) and using human induced pluripotent stem cells (Panula et al. 2010). In 2014, an Israeli and UK research team developed human primordial germ cells, using human embryonic stem cells. Primordial germ cells appear very early in embryo formation and go on to become egg and sperm (Irie et al. 2015; Cyranoski 2014). Then, in 2018, a team of Japanese scientists turned human blood cells into stem cells and subsequently into cells closely resembling human oogonia, an intermediate embryonic precursor for human oocytes. While an important feat, the oogonia, which were produced in mouse ovary organoids, were too immature to be fertilized to create an embryo (Yamashiro et al. 2018). Hence, as of 2019, human pluripotent stem cells have been induced into primordial germ-like cells, but further development into mature germ cells has not been achieved. The ability to reprogram human induced pluripotent stem cells into stem cell–derived gametes would enable scientists to develop gametes from the somatic cells of a prospective parent and thereby establish a genetic link. In contrast, human embryonic stem cells, unless they are generated through reproductive cloning, which entails a very arduous and unreliable process, carry the genes of the embryo from which they were derived. The possibility of having a genetic linkage to prospective children would likely make the development of gametes from human induced pluripotent cells considerably more attractive to potential parents than their development from human embryonic stem cells. Henry Greely, whose book anticipates a future of sexless reproduction through the development of pluripotent stem cell– derived gametes, acknowledges that going forward into such a future would likely depend on the ability to use human induced pluripotent stem cells or on some other method of creating stem cells derived from prospective parents’ own genetic material (Greely 2016, 127). However, as discussed in Chapter Two, human induced pluripotent stem cell derivatives have been shown to have far more mutations and alterations than human embryonic stem cells, some from the adult cells from which they are derived and others from the process of derivation, which raises fundamental questions about their appropriateness for clinical applications, most particularly for reproduction. This issue will be discussed further below.

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There are few informed estimates of how long it will take before researchers can develop functional (but not necessarily safe) human gametes from pluripotent stem cells. Estimates to date have usually been too optimistic. In 2008, the Hinxton Group, an international ethics and law consortium on genetics and stem cells, anticipated that the derivation of human eggs and sperm from pluripotent stem cells in whole or at least in part would take place within five to 15 years (Hinxton Group 2008). Also in 2008, the British Scientific and Clinical Advances Group, a committee of the Human Fertilisation and Embryology Authority, considered that the timescale for deriving gametes for treatment would be five to ten years. It was the view of members that the timescale for deriving sperm from stem cells would be shorter than for deriving eggs (Human Fertilisation & Embryology Authority 2009, 4).

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Potential Applications Pluripotent stem cell–derived gametes would provide a valuable research tool to gain a better understanding of the mechanisms of gamete development, something about which relatively little is known. Primordial germ cells go through a multi-stage process to generate spermatozoa or oocytes. Practical and ethical constraints associated with procuring earlystage human gametes have constituted a significant obstacle to addressing questions about the role of specific genes in early germ cell development and the interactions between germ cells and somatic cells. This knowledge would be relevant for preventing and treating infertility, genetic disease, and some cancers (Hinxton Group 2008). The availability of stem cell–derived gametes would also provide a plentiful supply of embryonic germ cells for scientific development and open the early stages of human development to observation and experimentation. Success in deriving human eggs in vitro would also reduce the need to solicit women to donate eggs for research purposes and save them from the health risks related to ovarian stimulation and egg extraction. The fertility drugs used for this purpose can cause side effects such as bloating, abdominal pain, and mood swings, and possibly result in a serious condition termed ovarian hyperstimulation. Ovarian hyperstimulation can cause severe abdominal pain, bloating, nausea, vomiting, and impaired kidney function (Melo-Martin 2016, 170). If successfully derived and also shown to be safe for use – two big ifs that seem unlikely – pluripotent stem cell–derived gametes could also provide a means to treat infertility problems. Infertility is a clinical condition that affects an estimated 15 percent of heterosexual couples of

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reproductive age (Moreno, Míguez-Forjan, and Simón 2015, 33). Individuals may be unable to produce gametes naturally due to organ deficiencies, disease, injuries, or cancer treatments, and therefore to have genetically related children. Menopausal women, including women who have undergone premature menopause, also cannot continue to reproduce naturally. Moreover, assisted reproductive technology techniques are not successful for an estimated 30 percent of infertile patients. Currently the only option for many couples is to adopt a child or to use donated gametes, but most prospective parents would much prefer having a genetically related child (Kashir et al. 2012). Some analysts anticipate that pluripotent stem cell– derived gametes could democratize reproduction while others propose that stem cell–derived gametes could even end infertility (Smajdor and Cutas 2015, 9). But for safe human gametes to be developed from induced pluripotent stem cells would require that the various scientific issues associated with induced pluripotent stem cells discussed in Chapter Two be successfully addressed – which at this point seems unlikely. Some analysts have also pointed out that, if pluripotent stem cell– derived gametes are successfully developed and deemed safe to use, some persons who are not infertile might also want to use this technology. This might include same-sex couples, individuals without partners, couples with inheritable genetic problems that cannot be eliminated using current screening technologies, and post-menopausal women (Kashir et al. 2012). There has also been speculation about the possibility of deriving eggs that could be used for reproduction from XY (chromosomally male) cells and/or developing sperm from reproductive purposes from XX (chromosomally female) cells, though these possibilities have been discounted by some sources (Hinxton Group 2008). If it were to be proven to be possible, a single individual could serve as the source of both egg and sperm. Doing so to initiate a pregnancy would be akin to human cloning and, like human cloning, viewed as ethically problematic by most people. It would also subject the child to a higher risk of genetic problems from recessive genes. Beyond these applications, Henry Greely envisions a future in which pluripotent stem cell–derived gametes are the basis of a reproductive process he terms “Easy PGD.” He predicts that advances in genetic knowledge will facilitate cheap, accurate, and fast sequencing of the entire genome of an embryo and will provide an increasing understanding of how versions of that sequence would translate into the disease risks, physical characteristics, behaviors, and other traits of the child a particular embryo would develop into. In his scenario, prospective parents with the financial means to do so would create hundreds or perhaps even thousands of embryos, have them sequenced, eliminate the embryos potentially affected

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by disease, and then select for implantation the embryo(s) that carry the traits most attractive to them. However, I think it is unlikely that PGD would ever be able to provide the detailed information Greely envisions, especially since many of the characteristics of interest would be shaped not by single genes but by large networks of genes, each making small contributions. Greely assumes that a population primed to have biologically related children would welcome a technology that overcomes the limitations posed by increasing maternal age and other factors. He also anticipates that the thriving and little-regulated for-profit fertility industry in the United States would be eager to accommodate them. He additionally expects that the procedure would be covered by health insurance (Greely 2016, 150–52), but, given the current limitations of coverage for expensive reproductive services, this seems doubtful. For all these reasons, Greely’s scenario is unlikely to occur.

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Safety Issues Safety is a critical factor when evaluating whether to adopt any new medical therapy, and it would be especially vital for a new reproductive technology that would affect not only the immediate child but future generations as well. The welfare of the child and of future generations of children, not the preferences of prospective parents, should be the paramount consideration. Hence the assessment of any new reproductive technology requires proceeding with extreme caution – or, to put it another way, the adoption of a strong version of the precautionary principle to protect the well-being of a future child. The potential damage would be serious and irreversible, and therefore the onus to prove that this technology is safe should be on the researchers developing pluripotent stem cell–derived gametes and the regulatory agencies evaluating them. In this regard, it is concerning that there is a history of innovations in medically assisted reproduction having been introduced into clinical practice without sufficient preclinical research or formal clinical trials to evaluate their effectiveness and safety (MeloMartin 2016). Consideration of the clinical use of pluripotent stem cell–derived gametes should depend on the ability to identify and address its long-term and multi-generational consequences for the child(ren) who will be born through this technology, in order to assure that it poses little risk over existing alternatives. We are currently a long way from that standard with pluripotent stem cell–derived gametes, and we may never get there. There are many potential risks. Children conceived through stem cell–derived gametes might suffer serious genetic anomalies or health impairments. Even

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if stem cell–derived gametes resemble functional gametes, they may not be fully normal. For example, the development of an embryo through this technology might be affected by imprinting errors that are not apparent (Smajdor and Cutas 2015, 12). A significant problem in assessing risks is the limit on our knowledge about the way gametes develop naturally. Given that the mechanisms of differentiation and maturation of spermatozoa and ova have not been fully elucidated, it is possible that pluripotent–derived germ cells may not have or be able to have the full functionality of human sperm and eggs. For example, the implications of erasing and resetting imprinting patterns to facilitate reproduction are not known (Suter 2015, 97). Also, while we can and should conduct extensive animal testing, particularly for this technology on large mammals including nonhuman primates, we cannot assume that what works without complications or heightened risks in one species will work similarly in humans, given the significant differences in our reproductive systems. Unintended genetic mutations could occur during the process of programming the gametes, particularly if combined with genome editing. With safety considerations in mind, it is concerning that gametes derived from human induced pluripotent stem cells would likely be preferred by prospective parents on the basis that these gametes would enable them to have a genetic link with their future offspring, whereas those generated from embryonic stem cells ordinarily would not. As discussed in Chapter Two, induced pluripotent stem cells have been shown to have far more abnormalities than human embryonic stem cells, some from the adult stem cells from which they are derived and some from the derivation process used to produce the cells. Additionally, induced pluripotent stem cells have been shown to retain an epigenetic memory and residual characteristics of the somatic cells from which they were derived. They also fail to reprogram cell methylation patterns (Garber 2013; Ma et al. 2014). That reprogrammed human induced pluripotent stem cells do not go through the fertilization process as human embryonic stem cells do could also be a problem with developing gametes from these cells (Garber 2013, 483). To provide an additional caution about the use of these cells for reproductive purposes, the first clinical trial using patient-derived induced pluripotent stem cells had to be suspended because of abnormalities found in the cells being used that did not exist in the patient’s cells from which they were derived. Also relevant, the research institute conducting the trial decided it was not feasible to continue to try to develop patient-specific induced pluripotent stem cells because of the time needed to prepare them and the cost involved (Garber 2015). Without using patient-specific cells as the

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starting material, gametes developed from human induced pluripotent stem cells would not provide the genetic linkage between parents and child. It may be, though, that some prospective parents would be willing and able to spend some $1 million to derive induced pluripotent stem cells and, then, gametes from their own skin or blood, but this would be very unusual. It would be possible to use human embryonic stem cell–derived gametes in order to maintain a genetic link with future offspring by developing the embryonic stem cells through cloning. A few scientists have derived human embryonic stem cells via nuclear transfer or cloning, the same process used to create Dolly, the famous cloned sheep. However, it is expensive, difficult, and time-consuming to do so and the process requires many eggs (Cyranoski 2013). Also, the extra steps needed to derive the gametes would put them at greater risk of programming errors. Even if the use of stem cell–derived gametes is not proven to be safe and does not get the approval of the U.S. Food and Drug Administration or a comparable regulatory agency elsewhere, there is a risk that some unscrupulous fertility centers may be willing to offer patients the technology. The little-regulated and predominantly for-profit fertility centers in the United States have a history of offering untested technologies and, if expressly forbidden, of moving the service, along with their patients, to another country. The 2016 case of a New York–based clinic taking one of its patients to Mexico to treat her with an unapproved mitochondrial replacement technique constitutes one recent example (Couzin-Frankel 2016). He Jiankui’s 2018 genetic editing experiment on the embryos of twin girls, which were then implanted and brought to term, also shows the danger of rogue scientists, desirous of achieving a major breakthrough, proceeding with reproductive experiments without the technology being evaluated for safety or authorized by the relevant oversight agency. Research on pluripotent stem cell–derived gametes will likely continue to proceed, but clinical applications should be delayed, perhaps indefinitely, until their use is considered safe enough for clinical trials and then human applications. The dilemma will be how to make such assessments and what level of risk will be deemed acceptable. A safety assessment will require the development of more sensitive and comprehensive screens to identify anomalies in the pluripotent cells to be used and to evaluate gametes after they are developed. The development and application of biomarkers to ensure that pluripotent cell derived gametes are morphologically and functionally similar to natural gametes will constitute a central safety input. Another requirement is the ability to apply standards for proof of meiosis, a defining event of gametogenesis. Achieving meiosis in vitro has been a significant challenge (Handel, Eppig,

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and Schimenti 2014). Responsible use of stem cell–derived gametes will also require long-term safety studies in a variety of large-animal models, especially nonhuman primates, over multiple generations. Even with these safeguards in place, there will be considerable risks. Some advocates of going forward with the technology, like Henry Greely, assume that with several decades of work these hurdles will be surmounted (Greely 2016, 129), but I have doubts whether this inherently risky technology can ever become sufficiently safe for reproductive applications. In weighing the risks against the benefits of the use of stem cell– derived gametes for reproductive purposes, it is important to remember that there are other, less risky paths to parenthood for persons with reproductive limitations, such as adoption of children and use of donor gametes. Both of these options, however, have the drawback of not providing a genetic linkage between the parent(s) and child. But, as Inmaculada de Melo-Martin argues, satisfying the desire to have a genetically related offspring should not constitute a scientific priority, given the many pressing needs that exist (2016, 265). The Nuffield Council on Bioethics also questions the extent to which it is justified to invest in the development of pluripotent stem cell– derived gametes, given the risks and costs involved and the availability of alternatives to having a child (Nuffield Council on Bioethics 2016). I agree with them. There are also other alternatives for couples seeking to avoid the inheritance of genetic disorders. Preimplantation genetic diagnosis (PGD) can screen for chromosomal abnormalities and genetic mutations related to more than 200 conditions in a developing oocyte or embryo before transfer into a woman’s body to enable the selection of a healthy embryo while preserving a genetic relationship between prospective parents and the child (Stern 2014). Gene editing to repair a mutation in a human embryo may be a future possibility with fewer safety risks. Finally, with regard to safety, some ethicists and scientists may believe that increasing options for reproductive choice and the potential creation or selection of children with traits desirable to prospective parents warrant taking risks. Other ethicists have concluded that the risks stem cell– derived gametes pose to prospective children may be so severe that their use should be limited (Master 2005). Further scientific research and analysis will be required to determine the balance between the risks and benefits, and we will need to be cautious in the interim. Consistent with that caution, regulations must be developed for research in this area, preferably internationally or at least on a national level, rather than institutions being left to decide, as is the case now for pluripotent stem cell research. In addition, institutions should be required to institute regulations and oversight

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mechanisms before permitting such research to take place, so as to prevent unauthorized implantations.

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Ethical Issues The only way to determine the functionality of pluripotent stem cell–derived gametes and to establish their capacity for fertilization and early embryogenesis would be to use them to create embryos through in vitro fertilization. Pluripotent stem cell–derived oocytes would need to undergo functional tests using natural sperm to assess whether fertilization can occur, and if successful would create embryos. Pluripotent stem cell– derived sperm would have the same requirement. The creation and destruction of large numbers of embryos during this experimentation would pose problems for many persons, and that is likely to include more people than persons who imbue the embryo with full moral status. This research would also be blocked by regulations in some countries and would not be eligible for federal research support in the United States. Another issue is how long it would be scientifically necessary and ethical to allow these embryos to develop before destroying them, in order to determine their functionality. Beyond evaluating their capacity for fertilization, it would be important to examine whether these research embryos develop normal body plans and germ layer formation when compared with embryos developed from natural eggs and sperm. Doing so might require maintaining research embryos in vitro up to and possibly beyond the current 14-day limit (Bredenoor and Hyun 2017, 396). The permissibility of doing so would depend on whether the current debate about extending embryo research beyond the current 14-day rule results in the loosening of this standard. If so, some of the embryos that are eventually destroyed may be past the point of formation of the primitive streak, which again would likely be ethically problematic for many people, including some like myself who support human embryonic stem cell research. Proceeding with the development of pluripotent stem cell–derived gametes for potential clinical use without these precautions would risk the introduction of a technology with significant potential for human harm. But creating and destroying large numbers of embryos for research purposes would be morally, and in some cases theologically, objectionable to many people, especially since it may involve the creation and destruction of not just a few embryos but hundreds or even thousands. Even many of those who do not imbue the human embryo with full human status may still have moral qualms about such an instrumental treatment of human life and be concerned with the impact destroying large numbers of embryos would have

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on the preservation of a commitment to the sanctity of life (Green 2001, 79). Moreover, the anticipated scale of the numbers of embryos created and destroyed to develop and test stem cell–derived gametes may raise the specter of “embryo farming” and further exacerbate concerns about the devaluation of human life (Cohen, Daley, and Adashi 2017). Greeley’s scenario about sexless reproduction through the use of stem cell–derived gametes, discussed above, also anticipates that couples using this technology would routinely create and destroy large numbers of embryos during their embryo selection process. He envisions that a clinic would take a skin biopsy or another cell from each of the prospective parents, develop the number of gametes the parents-to-be decide to order, fertilize them, and then some five days after fertilization remove several cells from all of the thriving embryos for genetic analysis. After analyzing the embryos through prenatal genetic diagnosis, which he believes would then be more accurate and have expanded capacities for analysis, the prospective parents would receive genomic information on the health risks and cosmetic traits of each of the embryos that had been created. They would then be asked to select the embryo(s) they want to implant, and possibly a second or third choice in case the pregnancy does not take (Greely 2016, 191–96). The other embryos would presumably eventually be destroyed. While Greely believes that providing couples with expanded reproductive choice would be advantageous, Sonia Suter has a different perspective. She has written about the enormous challenges to reproductive decision making that would result from the potential capacity to create vast numbers of embryos for which prospective parents would then obtain extensive predictive information. According to Suter, the dizzying amount of predictive information about the health and traits of potential future children that would be made available and the attempt to choose embryos with the ‘best’ combination of genetic variants would overwhelm future parents. She cautions that, rather than beneficially expanding reproductive choice, this innovation has the potential to result in choice overload and paralysis. Like some other technological advances in reproduction, she worries that Easy PGD also has the potential to reinforce prejudices against those with disabilities or undesirable traits (Suter 2018). Some analysts also anticipate that pluripotent stem cell–derived egg and sperm could be used for germ line (inheritable) genetic modification to correct disease mutations, introduce disease resistance, or facilitate other forms of biological enhancement (Richens 2008, para. 3.6 and 3.7). Attempts to do so would raise other ethical issues. Pluripotent stem cell–derived gametes offer two potential approaches to enhancement. One would be to alter the gametes before implantation using gene editing

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techniques such as CRISPR/Cas 9. The second, the type of selection process that Greely envisions, would enable prospective parents to have a large number of stem cell–derived gametes made, use PGD to screen the embryos using these gametes, and then select among them to try to have a child without genetic problems (however that is defined) and with the traits they desire. This is the scenario portrayed in the 1997 movie “Gattaca”, in which “improved” persons born through a similar process of genetic selection have higher social status and more life opportunities than those born through natural means. Greely tries to reassure his readers that the process he describes would limit the degree of enhancement possible because prospective parents could only select among the genetic variants already biologically present in their genomes. Greely estimates that the use of stem cell–derived gametes, combined with prenatal analysis, might produce humans that are about 20 percent healthier and 10 percent better-looking and more talented (Greely 2016, 238–40). However, having children who were 20 percent healthier with 10 percent better traits, presumably intellectual as well as physical, would be a significant improvement, and when magnified over multiple generations it would confer an even greater advantage. Another consideration is that use of enhancement technologies would likely exacerbate social inequalities, because those most likely to take advantage and able to afford them would be the white, economically well-off couples who are currently the predominant users of reprogenetic technologies (Melo-Martin 2016, 15). This would enable those with the most resources to add to the many advantages their children already have. It could also magnify the differences among countries, depending on how many in their populations have access to these technologies. Importantly, the fundamental issues about whether it is ethical to try to enhance future persons have not been resolved. Many view efforts to do so as crossing an ethically inviolate line. Before proceeding in that direction, there would need to be meaningful discussions to reach a decision that involved a broader cross-section of the population than a single researcher or a small group of experts. As a caution, the 2017 international panel convened by the National Academy of Science approved the use of gene therapy and gene editing for somatic applications under carefully defined circumstances, but it recommended that genome editing for enhancement purposes not be allowed (National Academies of Sciences, Engineering, and Medicine 2017). Questions have also been raised about the impact the technology could have on our conception of parentage and the psychological impact that using stem cell–derived gametes would have on children born through

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this technology. Simply put, the adoption of a technology that alters the reproductive process in this way would also fundamentally alter the relationship between parents and their children. Several ethicists have warned that efforts to develop designer children would risk reducing the child to an artifact, a product of technical design. The parents would become designers and children their product. It could also raise questions about who the parents would be – the source of the biological materials used in deriving the gametes or the person gestating them? What would it mean psychologically for a child born through gametes developed from embryonic stem cells to learn that her progenitor never lived but was destroyed in the process of her creation (Smajdor and Cutas 2015)? Would it harm a child to learn that a parent’s skin cells technically were the founding material for her life?

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Existing Guidelines Very few countries have adopted regulations and guidelines that would be relevant to addressing the many issues that pluripotent stem cell derived gametes would raise. In 2009, the British Human Fertilisation and Embryology Authority determined that, under the HFEA Act, the development of in vitro derived gametes would be allowable for research but not for treatment. It also decided that the derivation of in vitro derived gametes for research purposes did not require a license from the HFEA, but that researchers who wished to use in vitro derived gametes to create an embryo in order to test whether they were capable of fertilization would require a license (Human Fertilisation & Embryology Authority 2009). HFEA continues to prohibit the use of pluripotent stem cell–derived gametes for human reproduction. In Japan, production of human embryos for research purposes, whether with natural or with stem cell–derived gametes, is only permitted in exceptional cases where the research has scientific significance and the relevant knowledge cannot be otherwise obtained. The anticipated benefits also have to be socially appropriate, and human safety must be assured. Additionally the policy requires that there are safeguards in place to avoid reducing humans to tools or means (Mizuno 2016, 380). The development of germ cells from pluripotent cells is permitted, but fertilization of these cells is not. At the urging of Shinya Yamanaka, the scientist who first developed induced pluripotent stem cells, Japan’s science ministry adopted a policy that expressly forbids “the implantation of embryos made with [induced pluripotent stem] cells into human or animal wombs, the production of an individual in any other way from [induced pluripotent

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stem] cells, the introduction of [induced pluripotent stem] cells into an embryo or fetus, and the production of germ cells from [induced pluripotent stem] cells” (Cyranoski 2008, 408). There are no regulations specifically addressing the development of stem cell–derived gametes in the United States, but then there is very little in the way of regulations for pluripotent stem cell research or for the fertility industry in general. The Dickey–Wicker Amendment, an appropriations bill rider attached every year since 1995, prohibits the Department of Health and Human Services from funding research for the creation of embryos for research purposes or for research in which human embryos are altered or harmed. These prohibitions do not apply to research funded outside of the federal government. In 2015, Congress adopted another rider that prohibits the FDA from approving any research in which a human embryo is intentionally created or modified to include a heritable genetic modification (Cohen and Adashi 2016). This last rider would not constrain privately funded research on stem cell–induced gametes, but it would block FDA approval of clinical trials on any enhanced embryos created with them.

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Reflections The introduction to this chapter noted that not all potential applications of pluripotent stem cells are ethical and appropriate. This chapter addressed the question of how gametes developed from pluripotent stem cells should be regarded if and when scientists are successful in generating functional stem cell–derived gametes, something that at this time is still questionable. Gametes developed from pluripotent stem cells would offer a significant new model for studying gamete formation and the fertilization process and could potentially help identify the causes and contribute to the treatment of fertility problems. For these reasons, it may be appropriate to go forward with the research. However, I agree with Annelien Bredenoor and Insoo Hyun’s assessment that “For now, the technique to generate gametes in vitro is far away from being sufficiently safe and effective and clinical applications remain remote” (2017, 396). They go on to reflect that this has the advantage of giving us time to understand and evaluate this technology (Bredenoor and Hyun 2017, 396). It is important to use this time to address the issues this potential technology raises: x Even in the best of circumstances, with the safety issues addressed, the development of pluripotent stem cell–derived gametes would raise many significant ethical and societal issues. Before proceeding,

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it would be important to determine whether this a direction that society wants to take and, if so, how these issues can be addressed. Developing and testing pluripotent stem cell–derived gametes is likely to be an expensive process. What are the justifications for investing the necessary resources to do so, especially when there are simpler and less expensive ways for prospective parents to have a child; and, if it is decided to go forward, should the resources for this purpose be predominantly invested by public or private sources? Should more be done to question the importance of preserving a genetic link between parents and children, given that it motivates much of the incentive to develop pluripotent stem cell–derived gametes (Smajdor and Cutas 2015, 16)? If scientists are able to develop functional human pluripotent stem cell–derived gametes, what level of risk will be acceptable in using them for reproductive purposes; and who should be able to make this determination: the prospective parents or the broader society? If scientists are able to develop functional human pluripotent stem cell–derived gametes, should there be any restrictions on their modification for the purpose of introducing enhancements? What can be done to prevent fertility clinics from attempting to use pluripotent stem cell–derived gametes before a regulatory body, such as the U.S. Food and Drug Administration, determines that they are safe and appropriate for human use?

Clearly, pluripotent stem cell–derived gametes do not currently offer a new path for human reproduction and likely will never do so. There are too many safety concerns and risks of harm to the children potentially born from their use. It is particularly concerning that induced pluripotent stem cell derivatives, which likely would be preferred by prospective parents desirous of having a genetic link with their offspring, have intrinsic problems that appear to render them inappropriate for clinical applications, let alone for reproductive purposes. It seems unlikely that the safety issues discussed in this chapter can be overcome. The process by which gametes develop naturally is complex and incompletely understood. Unintended genetic mutations could occur during the process of programming the gametes, particularly if doing so were to also involve genome editing for enhancement purposes. Given that the differentiation and maturation mechanisms of spermatozoa and ova have not been fully elucidated, it is possible that pluripotent–derived germ cells may not have or be able to have the full functionality of human sperm and eggs. Moreover, we may not be able to determine in advance what the risks would be for the women

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gestating fetuses developed from pluripotent stem cells. Animal trials, even with nonhuman primates, cannot provide conclusive evidence of safety in humans. And it is important to remember that the negative impact would not only be limited to the people born in a single generation. As noted in this chapter, there are many ethical concerns associated with the development and use of pluripotent stem cell–derived gametes for reproductive purposes. This technology would also encourage “Gattaca”like embryo selection efforts, as parents would seek their ideal child, and result in acceleration of the commodification of reproduction. Hence at present, and indefinitely into the future, I believe that pluripotent stem cell– derived gametes should not be used for reproductive purposes. A recently published article observes that the implications of scientific breakthroughs are rarely addressed in advance of their realization. The authors call for the conduct of thoughtful ante hoc deliberations on the prospect of developing pluripotent stem cell–derived human gametes, which they characterize as a disruptive technology in waiting. They have in mind the model of the participatory public engagement process used by the British Human Fertilisation and Embryology Authority to decide whether to approve mitochondria replacement applications. To advance doing so, they propose that learned societies, professional associations, bioethics enterprises, advisory bodies, national academies, and other qualified institutions contemplate this matter. Their goal is to minimize potential untoward post hoc regulations or statutory implications (Adashi et al. 2019). In contrast, I think it is important to begin ante hoc deliberations for the express purpose of establishing regulations and statutory provisions to proceed cautiously and to limit unauthorized uses of pluripotent stem cell– derived gametes for human reproductive applications. Given the potential risks that applications of pluripotent stem cell– derived gametes pose, regulations, preferably at global and federal or national levels, are needed before the research proceeds further. These regulations should apply to all research institutions and potential users, including fertility clinics. Preferably, these regulations would require authorization from a regulatory body such as an institutional Stem Cell Research Oversight Committee to fertilize the cells in a laboratory for research purposes. Importantly the regulations should categorically prohibit implantation to begin a human pregnancy until a national regulatory body authorizes doing so. Considering past problems with scientists and doctors violating reproductive guidelines, the regulations should also prescribe significant penalties for violations. As decisions are made about whether to proceed with the development of pluripotent stem cell–derived gametes, it is important to

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remember that these decisions may potentially affect human inheritance and the future of human society. Much more is at stake than the safety issues involved.

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References Adashi, Eli Y., I. Glenn Cohen, Jacob H. Hanna, Azim M. Surani, and Katsuhiko Hayashi (2019) “Stem Cell-Derived Human Gametes: The Public Engagement Imperative.” Trends in Molecular Medicine 25 (3): 165–67. Bredenoor, Annelien L., and Insoo Hyun (2017) “Ethics of Stem CellDerived Gametes Made in a Dish: Fertility for Everyone?” EMBO Molecular Medicine 9 (4): 396–98. Cohen, I. Glenn, and Eli Y. Adashi (2016) “The FDA Is Prohibited from Going Germline.” Science 353 (6299): 545–46. Cohen, I. Glenn, George Q. Daley, and Eli Y. Adashi (2017) “Disruptive Reproductive Technologies.” Science Translational Medicine 9 (372). Couzin-Frankel, Jennifer (2016) “Unanswered Questions Surround Baby Born to Three Parents.” Science, September. https://www.sciencemag.org/news/2016/09/unanswered-questionssurround-baby-born-three-parents. Cyranoski, David (2008) “5 Things to Know Before Jumping on the iPS Bandwagon.” Nature 452 (7186): 406–8. https://www.nature.com/news/2008/080326/full/452406a.html. Cyranoski, David (2013) “Japan to Offer Fast-Track Approval Path for Stem Cell Therapies.” Nature Medicine 19 (5): 510. https://www.nature.com/articles/nm0513-510. Cyranoski, David (2014) “Rudimentary Egg and Sperm Cells Made from Stem Cells.” Nature, December. https://doi.org/10.1038/nature.2014.16636. de Melo-Martin, Inmaculada (2016) Rethinking Reprogenetics: Enhancing Ethical Analyses of Reprogenetic Technologies. New York: Oxford University Press. Garber, Ken (2013) “Inducing Translation.” Nature Biotechnology 31 (6): 483–86. Garber, Ken (2015) “RIKEN Suspends First Clinical Trial Involving Induced Pluripotent Stem Cells.” Nature Biotechnology 33 (9): 890–91. Greeley, Henry T. (2016) The End of Sex and the Future of Human Reproduction. Cambridge, MA: Harvard University Press. Green, Ronald M. (2001) The Human Embryo Research Debates: Bioethics in the Vortex of Controversy. New York: Oxford University Press.

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Handel, Mary Ann, John J. Eppig, and John C. Schimenti (2014) “Applying ‘Gold Standards’ to in-Vitro-Derived Germ Cells.” Cell 157 (6): 1257– 61. Hendriks, Saskia, Eline A. F. Dancet, Ans M. M. van Pelt, Geert Hamer, and Sjoerd Repping (2015) “Artificial Gametes: A Systematic Review of Biological Progress Towards Clinical Application.” Human Reproduction Update 21 (3): 285–96. Hinxton Group, The (2008) “Consensus Statement: Science, Ethics and Policy Challenges of Pluripotent Stem Cell-Derived Gametes” (Accessed 23 May 2020). http://www.hinxtongroup.org/au_pscdg_cs.html. Human Fertilisation & Embryology Authority (2009) “Background Briefings – in Vitro Derived Gametes (Updated).” Human Fertilisation & Embryology Authority (Internet Archive, captured October 14, 2010). http://www.hfea.gov.uk/in-vitro-derived-gametes.html. Irie, Naoko, Leehee Weinberger, Walfred W. C. Tang, Toshihiro Kobayashi, Sergey Viukov, Yair S. Manor, Sabine Dietmann, Jacob H. Hanna, and M. Azim Surani (2015) “SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate.” Cell 160 (1): 253–68. Kashir, Junaid, Celine Jones, Tim Child, Suzannah A. Williams, and Kevin Coward (2012) “Viability Assessment for Artificial Gametes: The Need for Biomarkers of Functional Competency1.” Biology of Reproduction 87 (5). Katsnelson, Alla (2012) “Mouse Stem Cells Lay Eggs.” Nature, October. https://doi.org/10.1038/nature.2012.11545. Ma, Hong, Robert Morey, Ryan C. O’Neil, Yupeng He, Brittany Daughtry, Matthew D. Schultz, Manoj Hariharan, et al. (2014) “Abnormalities in Human Pluripotent Cells Due to Reprogramming Mechanisms.” Nature 511 (7508): 177–83. Master, Zubin (2005) “Embryonic Stem-Cell Gametes: The New Frontier in Human Reproduction.” Human Reproduction 21 (4): 857–63. McCormack, Kevin (2018) “Using Blood Stem Cells as Delivery Vehicles to Weed Out Hidden Cancer Cells.” The Stem Cellar: The Official Blog of CIRM, California’s Stem Cell Agency, November. https://blog.cirm.ca.gov/2018/11/07/using-blood-stem-cells-asdelivery-vehicles-to-weed-out-hidden-cancer-cells/. Mizuno, Hiroshi (2016) “Recommended Ethical Safeguards on Fertilization of Human Germ Cells Derived from Pluripotent Stem Cells Solely for Research Purposes.” Stem Cell Reviews and Reports 12 (4): 377–84.

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Moreno, Inmaculada, Jose Manuel Míguez-Forjan, and Carlos Simón (2015) “Artificial Gametes from Stem Cells.” Clinical and Experimental Reproductive Medicine 42 (2): 33–44. Munsie, Megan, Insoo Hyun, and Jeremy Sugarman (2017) “Ethical Issues in Human Organoid and Gastruloid Research.” Development 144 (6): 942–45. National Academies of Sciences, Engineering, and Medicine (2017) Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. https://doi.org/10.17226/24623. 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. Nayernia, Karim, Jessica Nolte, Hans W. Michelmann, Jae Ho Lee, Kristina Rathsack, Nadja Drusenheimer, Arvind Dev, et al. (2006) “In VitroDifferentiated Embryonic Stem Cells Give Rise to Male Gametes That Can Generate Offspring Mice.” Developmental Cell 11 (1): 125–32. Nuffield Council on Bioethics (2016) “Forward Look 2016” (Accessed 23 May 2020). https://www.nuffieldbioethics.org/wp-content/uploads/ NCOB-Forward-Look-2016-Longevity.pdf. Ohio State University, The (2015) “Scientist: Most Complete Human Brain Model to Date Is a ‘Brain Changer’.” Press release (Accessed 23 May 2020). https://news.osu.edu/scientist-most-complete-human-brainmodel-to-date-is-a-brain-changer/. Panula, Sarita, Jose V. Medrano, Kehkooi Kee, Rosita Bergström, Ha Nam Nguyen, Blake Byers, Kitchener D. Wilson, et al. (2010) “Human Germ Cell Differentiation from Fetal- and Adult-Derived Induced Pluripotent Stem Cells.” Human Molecular Genetics 20 (4): 752–62. Richens, Helen (2008) “Update on in Vitro Derived Gametes.” SCAG(05/08)01. Human Fertilisation; Embryology Authority, The Scientific; Clinical Advances Group; Decision (Accessed 23 May 2020). https://www.yumpu.com/en/document/view/24593117/scaghuman-fertilisation-and-embryology-authority. Smajdor, Anna, and Daniela Cutas (2015) “Artificial Gametes.” Background Paper for the Nuffield Council on Bioethics (Accessed 23 May 2020). https://www.nuffieldbioethics.org/wp-content/uploads/ Background-paper-2016-Artificial-gametes.pdf. Stern, Harvey J. (2014) “Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its Potential.” Journal of Clinical Medicine 3 (1): 280–309. Suter, Sonia M. (2015) “In Vitro Gametogenesis: Just Another Way to Have a Baby?” Journal of Law and the Biosciences 3 (1): 87–119.

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Suter, Sonia M. (2018) “The Tyranny of Choice: Reproductive Selection in the Future.” Journal of Law and the Biosciences 5 (2): 262–300. Yamashiro, Chika, Kotaro Sasaki, Yukihiro Yabuta, Yoji Kojima, Tomonori Nakamura, Ikuhiro Okamoto, Shihori Yokobayashi, et al. (2018) “Generation of Human Oogonia from Induced Pluripotent Stem Cells in Vitro.” Science 362 (6412): 356–60.

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CHAPTER EIGHT

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JUSTICE ISSUES IN STEM CELL THERAPY AND ACCESS TO ITS BENEFITS

A commitment to justice requires that when significant public funds and scientific expertise are invested in therapies that they bring significant potential public benefit, and as a 2018 editorial in Science magazine commented, “A staggering amount of public money has been spent on stem cell research globally” (Sipp, Munsie, and Sugarman 2018, 1275). Public benefit from a new therapy depends on the number of people who could be helped by the therapy, whether there are existing alternatives, and the seriousness of the medical problems that are being addressed. It also entails making the therapies once developed accessible and affordable to those in need of treatment with them. 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. One reason is that commercialization results in very high prices for most new medical therapies making them well beyond what most individuals can afford and private and public health insurers willing to cover. Given the significant public investment in pluripotent stem cell research and their potential to advance the health and well-being of many people, it is important this does not happen in the pluripotent stem cell field. As noted in Chapter One, the National Academy of Sciences identified the need for the just distribution of the potential benefits of embryonic stem cell research in its recommendations for the field (Institute of Medicine and National Research Council 2005, 55), and the International Society for Stem Cell Research (ISSCR) also shares this concern for justice. One of the fundamental ethical principles informing the 2016 Guidelines for Stem Cell Science and Clinical Translation issued by ISSCR 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

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Society for Stem Cell Research 2016, Section 3.5.2). ISSCR does not, however, offer guidance on how to accomplish these goals. An assessment of how justice concerns relate to the pluripotent stem cell field has many elements that will be discussed in this chapter. To begin with, Rebecca Dresser has questioned whether the allocation of government and private resources in stem cell research can be justified in terms of public health needs and the numbers of people who can be benefited. She is also concerned that investments in stem cell research come at the expense of what she considers to be more significant health priorities (Dresser 2010). Related to Dresser’s concern, there is the issue of which people and communities can potentially be benefited if therapies currently under development are successful. Some new therapies, for example gene therapies, seek to address disorders affecting small numbers of patients. Many of the genetic disorders that gene therapies seek to correct are rare diseases affecting less than 200,000 people in the United States. In contrast with Dresser, others have proposed that the investment in stem cells can only be justified if significant economic benefits from the development of stem cell–based therapies accrue to the public agencies which sponsored them. Policymakers in several states have proposed that the state and the taxpaying public’s interest should be reflected in the intellectual property requirements imposed on the recipients of the funds and/or payment of royalties so that the state can recoup its investment. However, pressures to patent and commercialize stem cell research and therapies can have detrimental consequences, particularly in undermining scientific collaboration, in promoting hype and false expectations, and in increasing the eventual pricing of the products developed (Caulfield 2010). Then there is the thorny issue of how to make these therapies affordable and accessible when they come to the clinic. This will take a major effort. It will not happen otherwise. CIRM had put forward some requirements for recipients of its grants, but as the chapter will explain, these were insufficient to accomplish this purpose. The pending proposal for a second round of funding for CIRM offers a more comprehensive plan to try to do so that will be discussed in this chapter. Finally, there is the question of timing, i.e. when the therapies are likely to be available. While this is not strictly a justice issue in the same sense as the others, many people are pinning their hopes on pluripotent stem cell–based therapies becoming accessible quickly for hitherto untreatable diseases and disorders with which that they, members of their family, or others that they care about are suffering. As noted in other chapters, often their hopes about the rapid development of therapies have been unrealistic.

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Moreover, the lack of approved treatments had led many patients to decide to try unapproved stem cell treatments promoted by unregulated clinics, often with them not aware of the status of the advertised therapies and the risks entailed of using them. Chapter Four discussed the resulting public health consequences. At several points this book has tried to explain why it is taking so long to develop pluripotent stem cell therapies. This chapter will conclude with some reflections on when at least a few of the therapies may become available.

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Social Justice and the Allocation of Limited Resources According to Rebecca Dresser, stem cell research raises questions about the appropriate allocation of government and private resources in biomedicine. She points out that stem cell research is just one type of promising research and neither the public sector nor the private sector can support every promising research area. Moreover, she assumes that funds invested in stem cell research will reduce the possibility of investments in other areas of health and medicine that she considers more potentially beneficial. She is concerned as well that much of stem cell research is aimed at understanding and trying to treat chronic diseases of aging, such as heart disease and neurological diseases, that have the possibility of extending the human life span but not improving well-being in earlier stages of life. She finds this problematic. While she acknowledges that stem cell research may also result in therapies for currently untreatable conditions that affect the young as well, she argues that many more people could be benefited through providing better health care than developing new stem cell therapies. She asks whether it is ethical to devote large sums of money to research, any field of research, when so many people in this country and elsewhere lack access to medical care that could provide longer and better lives (Dresser 2010). Dresser raises valid issues. For example, could the $3 billion dollars California has invested in stem cell research and other cutting-edge therapies have been more justly spent on improving its health care system? Even after the establishment of the Affordable Care Act and before the complications of the coronavirus pandemic several million Californians still lacked health insurance and many of those with coverage continued to be unable to afford needed treatments and medications. Or taking Dresser’s argument beyond California, could the whole NIH budget and thrust to fund research to develop new therapies be more justly invested in efforts to improve health care quality and access?

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It is difficult to answer these questions conclusively for several reasons. Firstly, at this time we do not know the outcomes of the investments in pluripotent stem cell research and clinical trials so we can only surmise what they may be and whom they will benefit. However, it is important to note that in contrast with gene therapy, which in most instances is trying to correct rare disease mutations affecting a small patient population, many of the pluripotent stem cell therapies under development could potentially improve the lives of fairly large numbers of people, not all of whom are afflicted by chronic diseases of the aging. Type 1 diabetes, retinitis pigmentosa, spinal cord injury, cancer treatment, and blood disorders are not specifically diseases of the aging. Which diseases and disorders pluripotent stem cells are likely to treat will be discussed in the next section of this chapter. Moreover, given the aging of the population in this country and elsewhere in the world, treating chronic diseases of the aging could improve the lives of a significant proportion of the population and also enable them to make a continuing societal and economic contribution. Secondly, there is little likelihood that even if the public investments in pluripotent stem cell research had not been made that equivalent funds would have been invested in improving health care access and availability in general or specifically for the most disadvantaged groups. The failure to achieve universal health care in the United States is not primarily a matter of the economics of health care reform or the lack of investment. The U.S. health care system is already the most expensive in the world even though it does not provide universal health care or always offer a good quality of care (Dickman, Himmelstein, and Woolhandler 2017). The failure to offer universal coverage is primarily due to the absence of political will to do so and the lack of a strong demand in the population. Racism has also played an important role in the failure to build a strong safety net that encompasses all races and ethnic groups (Porter 2020). Nor would the amount of the investments in stem cell research if diverted to the delivery of health care have been able to make a significant difference for the millions of people who lack health insurance and the others who cannot afford the deductibles and co-pays for medication and therapies related to their health insurance. Thirdly, to truly improve health care access and the quality of health care would require an entire remake of the U.S. health care system to make it more equitable and more responsive to the health care needs in the country. To achieve greater health care equity in the U.S. would require reforms that institute a non-market financing scheme that treats health care as a human right and not as a profit-making commodity as it currently is. As the history of the debate about health care policies and potential reforms in this country and elsewhere indicate, these issues are entangled with racial

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discrimination, party politics, and ideology. Neoliberal ideology, which has been dominant in the U.S. and to a lesser extent elsewhere for several decades, conceptualizes health care as a for-profit commodity and not a right or a public good (Chapman 2016). Fourthly, as the disproportionate harms of the Covid-19 pandemic have underscored, widening economic inequality in the U.S. and many other countries has been a major determinant of the increasing disparities in health outcomes. Income-related disparities in access to care are far more significant in the U.S. than in other wealthy countries and even some upper middle-income countries (Dickman, Himmelstein, and Woolhandler 2017, 1432). Improving access to health care without major reforms reducing income disparities and equalizing many of the other social determinants of health will not be enough to reduce these disparities.

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Public Health Needs and the Diseases and Disabilities Likely to Be Treated through Pluripotent Stem Cell Therapies The diseases and disorders likely to be addressed by pluripotent stem cell therapies are an important consideration in assessing justice perspectives. As noted above, Rebecca Dresser is concerned that the benefits will disproportionately accrue to those who are suffering from chronic diseases of aging. She is correct that pluripotent stem cell interventions are likely to disproportionately, but not solely, benefit this group. However, I think the more important issue from a justice perspective is how many lives could potentially be improved and benefited by future stem cell–based cures, especially for serious diseases and disabilities for which there are not currently alternative therapies. A report by researchers at the University of Southern California’s Leonard D. Schaeffer Center for Health Policy & Economics examining the value of hypothetical future stem cell interventions from research funded by CIRM anticipates that the therapies could improve the lives of millions of people in California, particularly those over the age of 50 (McCormack 2019). Whether this will be the case may depend on CIRM having the resources needed to continue development of these therapies. The broader implications of these investments may also be contingent on initiatives that California undertakes to make the therapies affordable and accessible in the state and how California shares the benefits of its investments with other states and countries. There is little indication that CIRM has given much thought to making the benefits of its investments more broadly available outside of California.

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As the data in Chapter Six indicate, pluripotent stem cell–based therapies are currently in clinical trials for age-related macular degeneration, Stargardt dystrophy, retinitis pigmentosa, Parkinson’s disease, spinal cord injury, diabetes mellitus type 1, severe ocular surface diseases, heart disease, graft-versus host disease, and cancer treatment. Most of these conditions cannot currently be cured with existing therapies. To provide a brief profile of these diseases: Parkinson’s disease: Neurological disorders are a leading source of disability globally, and Parkinson’s disease, the second most common neurodegenerative disorder after Alzheimers disease, is the fastest growing neurological disorder. Between 1990 and 2015 the number of people with Parkinson’s disease doubled to over 6 million, and the incidence is projected to double to over 12 million by 2040. Today there is no cure available, and medications only provide partial relief for the coordination and movement problems that characterize Parkinson’s disease. Moreover, existing therapies do not stop the progressive course of the disease (Dorsey et al. 2018). Type 1 Diabetes: Type 1 Diabetes, also known as Juvenile and Insulin Dependent Diabetes, is a chronic autoimmune disease that affects approximately 1.25 million Americans, with 40,000 new diagnoses each year. Although the total global incidence of type 1 diabetes is not known, the IDF Diabetes Atlas 2019 lists the global incidence in the age group of 0–19 years as 1,106,500 with an annual increase of 132,600 newly diagnosed cases. Type 1 Diabetes occurs as a result of the body’s immune system destroying its own pancreatic beta cells that are needed to produce the vital hormone insulin that regulates blood sugar levels in the body. Current treatments consist of blood sugar monitoring and multiple daily injections of insulin. When not well-managed, and sometimes it is difficult to do so, serious complications develop that threaten health and can endanger life (World Health Organization 2016; Villa 2019; European Society of Cardiology 2019). Age-related macular degeneration: AMD causes progressive vision impairment and loss resulting from the deterioration of the macula, the central part of the retina. It is the main cause of visual impairment and blindness in Europe. It is estimated to affect more than two million people in the U.S. and 67 million people in the European Union. Due to population aging these figures are expected to increase considerably. There is no treatment to cure age-related macular degeneration (Li et al. 2020; National Eye Institute, n.d.). Stargardt dystrophy (Stargardt macular degeneration): Like AMD, Stargardt dystrophy causes progressive vision impairment and loss

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resulting from increasing damage to the macula. Unlike AMD, Stargardt dystrophy is a single-gene disorder that begins in childhood or adolescence. It is estimated to affect 1 in 8,000 to 10,000 persons. There are no treatments currently available (National Eye Institute, n.d.). Retinitis pigmentosa: Retinitis pigmentosa is another hereditary eye disease which in this case results in the gradual degeneration of the retina leading to the loss of sight. It is thought to affect 1 in 4,000 people in the U.S. and globally. While there are no current treatments, there are ongoing gene therapy trials as well as pluripotent cell–based treatments in trials (National Eye Institute, n.d.). Spinal cord injuries: Spinal cord injuries interfere with normal motor, sensory, or autonomic functioning. Depending on how severe the injury is and where the physical damage is located, spinal cord injuries can result in complete paralysis or partial disabilities with no therapies available. There are fewer than 200,000 cases per year in the U.S. (National Institute of Neurological Disorders and Stroke, n.d.). Cancer: Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Cancer is a major public health problem worldwide and the second leading cause of death in the U.S. In 2018 there were 17 million new cancer cases and 9.5 million deaths globally, and it is estimated that by 2040 these figures will grow to 27.5 new cases and 16.3 deaths due to the growth and aging of the population (American Cancer Society 2020). There are a range of therapies applied to try to address different forms of cancer with varying degrees of success. In addition to the current off-the-shelf induced pluripotent stem cell immunotherapy product in clinical trials, cutting edge cancer treatment initiatives supported by CIRM include CAR T (chimeric antigen receptor T cells) and antibody therapy (McCormack 2020). Heart disease: Like cancer, heart disease, a range of conditions that affect the heart, is the leading cause of death in the U.S. and a major public health problem worldwide. And like cancer, the incidence is very likely to increase as the population continues to grow and age. Coronary artery disease, a form that can lead to heart attacks, is the most common type in the U.S. (Centers for Disease Control and Prevention, n.d.). There are a range of different types of treatments available of varying degrees of success. Graft versus host disease: Graft-versus-host disease is a syndrome characterized by inflammation in different organs that is a common complication of bone marrow and other kinds of transplants. It can be acute or chronic and in its most acute form causes a rejection of a transplant.

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While there are no current preventive measures or therapies a gene therapy as well as a pluripotent stem cell–based treatment is in clinical testing.

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Patenting Issues Patents provide a legally defined right in a specific country that recognizes the patent holder’s exclusive ownership and control over the technology, the therapy, the product, or the process in question during the period of the patent’s duration, often 20 years but sometimes less. Patent laws enable patent holders to make it difficult for other researchers to obtain licenses critical to their work thus potentially blocking follow-on research based on a foundational technology (Feeney et al. 2018). Patents also enable the patent holder to set the cost for a product which usually results in a higher cost, often a much higher cost, for products that are developed. Pluripotent stem cells are one such foundational technology, and in this regard it is relevant to note that the Wisconsin Alumni Research Foundation (WARF), a non-profit foundation that manages intellectual property generated by researchers at the University of Wisconsin, owns three key patents for human embryonic stem cells based on the pioneering work of James Thomson making it is necessary for any researcher planning to use human embryonic stem cells to receive a license from WARF. Although there were initial concerns that WARF’s patents would block research and the development of therapies from human embryonic stem cells or make it prohibitively expensive, WARF has progressively liberalized its licensing and authorization practices for non-profits although it still demands payments from commercial entities. Also, it is likely that significant therapeutic applications of human embryonic stem cells are unlikely to occur until after WARF’s patents expire in the next few years (Golden 2010). Because patent exclusivity enables the patent holder to determine the price to be charged and frequently patent holder set high prices for their products, this has often made innovative medical therapies unaffordable. Escalating prices for prescription drugs and the very high cost of innovative medical therapies have contributed to the rise of health care costs and made many medicines and therapies unaffordable both for the patients and for public insurance programs. To provide a few examples, direct acting antiviral therapies represent a major breakthrough for treating hepatitis C, the most common bloodborne infection in the United States, which affects an estimated 3 million mostly poor persons. Sovaldi, the initial antiviral drug developed to treat hepatitis C came onto the market with a list price of $1,000 a pill adding up to $84,000 per person for the standard 12-week

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treatment course and not because it was so expensive to develop and manufacture. State Medicaid programs therefore rationed access and chose to cover small fractions of the infected population that would benefit from the drug because they could not afford to do otherwise (Chapman and Buckley 2017). The ever-rising cost of cancer drugs in the past 20 years has led some oncologists to believe that these prices have crossed the moral line between reasonable profits and profiteering. Oncologists warn that many cancer patients may die because they cannot afford the $20,000 to $30,000 copays per year, let alone the full cost of the treatment (Kantarjian et al. 2014). Many of the outrageously priced therapies were initially developed through grants from public funders to academic researchers. The research that led to Gilead Science’s Sovaldi, the antiviral medication for hepatitis C, had the benefit of NIH funding (Chapman and Buckley 2017) as did Novartis’s Kymriah, a CAR-T cancer therapy for childhood leukemia with a $475,000 price tag for a single application (Silverman 2017). Under the Bayh–Dole Act (the Government Patent Policy Act of 1980) recipients of grants from U.S. government agencies may retain patent rights for their inventions (U.S. Government Printing Office 35 U.S.C. § 202). Governments in many other countries have similarly decided to allow the inventor to retain principle or exclusive rights assuming this incentive for product development would increase the country’s economic competitiveness. The Bayh–Dole Act thereby established the right of individuals and institutions receiving federal research grants to commercialize their discoveries by taking out patents and issuing exclusive licenses for use of these patents, but the statute also spelled out a range of conditions under which the government could exercise march-in rights to require the patent holder to grant licenses on reasonable terms to others to employ the patent. According to the law, the government may do so when “action is necessary to alleviate health or safety needs which are not reasonably satisfied” (U.S. Government Printing Office 35 U.S.C. § 201). However, the U.S. government has been reluctant to exercise its march-in rights. As of 2015, NIH had reviewed five petitions requesting NIH to exercise its march-in rights for medical products. Three of these requests were to reduce the high prices of drugs, one to relieve a drug shortage, and one pertained to a potentially patentinfringing medical device. Even though several of these petitions seemed to fit the criteria set down by the statute, NIH summarily rejected all of these requests to exercise its march-in rights (Treasure, Avorn, and Kesselheim 2015). In 2016 51 members of Congress asked NIH to use its authority under the Bayh Dole Act to rein in high drug prices, but NIH again refused to do so (Love 2016).

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In contrast, the regulations adopted by the CIRM that apply to its grantees incorporate several initiatives that offer a preferable model for publicly funded research patenting that conforms more with the public interest. These regulations not only bind CIRM grantees and loan recipients but also apply to their grantees’ collaborators and licensees. Like the Bayh– Dole legislation, CIRM permits researchers with CIRM grants to patent their discoveries, but unlike Bayh–Dole, CIRM’s intellectual property provisions require that once their products are commercialized grantees must share revenue with the state treasury. CIRM is not the only state stemcell funding program that has such a revenue-sharing provision. The Connecticut stem-cell program does so as well. CIRM’s policy distinguishes between nonprofit grantees, such as universities and research institutes, and for-profit entities. While the royalties required from profits exceeding $500,000 are steep in both cases they are less so with regard to the rates for nonprofit grantees (Institute of Medicine 2013, 112). It is too soon to know whether CIRM will be able to recoup part of its investment through payment of these royalties. CIRM’s grantees and their exclusive licensees are also required to submit plans to CIRM indicating how they will assure access to any drug resulting from CIRM funded research to Californians who have no other means to purchase the drug. This requirement has been one of the most controversial aspects of CIRM’s intellectual property provisions. Industry representatives argued that the requirement will make investors less interested in licensing CIRM funded inventions, while legislators criticized the access provisions as too weak to ensure meaningful access for the uninsured (Institute of Medicine 2013, 116). I tend to agree with the legislators’ concerns. CIRM also holds march-in rights that allow it to override license agreements for CIRM-funded inventions. These march-in rights are broader both in the entities to which they apply and in their scope than those the federal government holds under the Bayh–Dole legislation. CIRM’s marchin rights allow it to enter into license agreements on behalf of a grantee or its exclusive licensee under three circumstances. These are (1) the failure to exercise reasonable efforts to achieve practical application of the invention; (2) the failure to submit or comply with an access plan; and (3) the unreasonable failure to use a CIRM-funded invention to alleviate a public health emergency (Institute of Medicine 2013, 117–18). However, these march-in rights will only be effective if CIRM applies them aggressively. Since no CIRM funded therapy has as yet have entered the market, it is too soon to know if it will.

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To achieve social justice goals it would also be important that an access plan also have an explicit reasonable pricing clause with mandatory guidelines that would apply to all sales, and not just CIRM’s policy of the Californians who have no other means to purchase the drug. This is particularly important because as noted above new technologies and therapies typically have prohibitive costs. Also, without a requirement for universal application patent holders may try to make up for revenue lost because of a required access plan by raising the price for other users (Chapman 2018). The section of this chapter discussing provisions of CIRM’s proposed 2020 proposition for renewal identifies that it incorporates more effective initiatives toward this objective.

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The Dilemmas of Commercialization Pluripotent stem cell research and the development of therapies are taking place in the context of a market system with its attendant pressures for commercialization. Commercialization, managing or operating something for financial gain, makes it more difficult to achieve affordability, a key justice requirement. As Peter Bach notes “Nowadays, the reality of exorbitant drug pricing overshadows even the most exceptional stories of drug efficacy… Hand clapping for science is now inextricably linked to hand wringing over affordability. Drug prices are increasing more rapidly than their benefits” (Bach 2015, 1797–8). Complicating the situation, as noted in Chapter Four, the process of moving stem cell research from the laboratory into clinical trials and then the market is costly and requires a level of resources that the university based researchers and small biotechnology companies, which to date have been the primary developers of pluripotent stem cell treatments, often cannot afford. Translational research, particularly Phase III clinical trials which require large numbers of participants, has even been referred to as “the valley of death.” In Chapter Five it was noted that even CIRM, with its extensive resources, has not been able to underwrite the full cost of the three stages of clinical trials and therefore has sought corporate partnerships through its Industry Alliance Program. CIRM has also assumed that to become available to patients it is necessary for the therapies whose development it sponsors to be commercialized by a pharmaceutical or biotech company (Villa 2020). CIRM projects have been partnered and licensed to companies and in other instances projects that received CIRM funding during early stages of development have led to the creation of a spin-out company eventually acquired by a leading biotech corporation (Sambrano and Millan 2020, 481). CIRM heralded as a significant validation

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for its early support when Forty Seven Inc’s anti-cancer therapy was bought for nearly $5 billion by Gilead (McCormack 2020). However, while corporate financing may facilitate bringing a pluripotent stem cell therapy to market, commercialization with its attendant seeking of financial profit undermines the prospects for achieving affordability, a key justice requirement. Also relevant to this issue, a survey of pluripotent stem cell research funding guidelines and the project evaluation criteria of major public funding organizations in the European Union, the United Kingdom, Spain, Canada, and the United States revealed subtle and not so subtle pressures to commercialize research. Policies included making increased funding available for commercialization opportunities, assistance for obtaining intellectual property rights, and legislation mandating commercialization. These policies encouraged universities and university-based researchers to pursue for-profit and commercial opportunities (Lévesque et al. 2014, 455). To provide some examples, the U.S. National Institutes of Health (NIH) requires the researchers it funds to disseminate unique research resources to promote the advancement of science but also to commercialize research to demonstrate economic benefits to taxpayers. Grant projects seeking over $500,00 per year must submit a data sharing plan. Some of the data sharing plans of the various NIH institutes stipulate that research data must be available within one year of publication while others are more openended. At the same time researchers are expected to patent and commercialize their findings (Lévesque et al. 2014, 465) even though these two objectives seem incompatible. Similarly, the 7th Framework Programme of the EU in force between 2007 and 2013 used the notion of “European added value” as a qualification criterion for funding that required research sharing within the EU. It also encouraged grant recipients to retain exclusive rights and licensing to facilitate commercialization (Lévesque et al. 2014, 459). The Medical Research Council in the UK which funds the Centre for Regenerative Medicine has a data sharing policy that valuable scientific data from MRC funded research should be made available to the scientific community with as few restrictions as possible while also making it clear that this policy is not intended to discourage the filing of patent applications in advance of publication (Lévesque et al. 2014, 460–61). In addition, public funding of stem cell research in the UK is driven by a wider strategic goal to strengthen public–private partnerships and collaborations between universities and industry (Lévesque et al. 2014, 465). CIRM also has these dual requirements with regard to data sharing of biological materials, including newly derived pluripotent stem cell lines

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after publication, but only with other researchers in California, presumably to facilitate the development of medical treatments and cures for residents of the State (Lévesque et al. 2014, 466). Its commercialization imperative, discussed above with reference to its intellectual property policy, is intended both to ensure therapies become publicly available and to enable the State to reap financial benefit from royalties. Other than speculation about the potential adverse impact of patents on the research environment, specifically whether the growing number of patents held by a diverse group of stakeholders will result in the development of a patent thicket that will be a barrier to progress in the field, there has only been limited consideration of the potential adverse impact of commercialization (Caulfield 2010, 306–7). Nevertheless, there is some evidence that commercialization pressure could have an adverse influence on the sharing of data and potential collaborations (Caulfield 2010, 308). Importantly, commercialization may also have the potential to damage public trust and support. For example, studies have shown that the public has less trust in scientific researchers who are in the private sector or receive funding from the private sector (Caulfield 2010, 308). Whether this carries over to the pluripotent stem cell field is not yet known. Several researchers have raised questions about the commercial viability of future stem cell therapies and whether it will be possible to build a major industry in this field (Caulfield 2010, 306; Little, Hall, and Orlandi 2006). It is too soon to determine whether this will be the case. To date the gene therapy field, the closest analogue to a potential stem cell field, has had both a commercial failure from a very high price and a small potential patient pool and some commercial success, such as Novartis has received from Zolgensma which treats pediatric spinal muscular atrophy. More than 60 gene therapies are currently in development, with sales forecast to reach $15 billion by 2024 (Gardner 2019).

Potential Public Economic Benefits Policy arguments supporting public stem cell research funding have often used anticipated economic benefits as a key rationale. Timothy Caulfield proposes that the socially controversial nature of the field, particularly human embryonic stem cell research, and the vocal and politically active character of its opponents have inclined proponents to make such overly optimistic economic claims (Caulfield 2010, 303). In the context of pluripotent stem cell research economic benefit is often premised on curing diseases and thereby reducing health care costs and improving productivity,

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generating tax revenues and royalties, and stimulating the growth of the biotech sector (Caulfield 2010, 305). As noted in Chapter Five, this certainly was the case with the claims made in the 2004 campaign to approve Proposition 71 in California. Proponents anticipated such economic returns as job creation and increased tax revenue as well as the receipt of generous amounts of royalties from the therapies developed. The potential trade-off between the receipt of royalties and the possible need to raise the cost of the products to pay for it making the therapies less affordable was never discussed. In 2007, three years after the approval of Proposition 71, three California health and science researchers knowledgeable about the stem cell field proposed a series of benchmarks to evaluate CIRM funding so that California voters could assess the impact of their investment. Their article discussed four general categories to assess. Firstly, stem cell research could lead to the development of less expensive therapies to replace currently expensive treatments and thereby improve the health of the population while reducing the resources expended to care for the sick. They noted that new therapies that are expensive or do not replace current treatments could still generate benefits in the form of improved societal health. Secondly, they suggested considering the opportunity costs of the investment, specifically whether the returns from stem cell research are larger than the returns from other potential investments. Thirdly, they raised the issue of whether and how the benefits are divided, that is, who are the winners and losers. Fourthly, they addressed issues related to intellectual property and whether the intellectual property developed with CIRM funding would provide a direct financial return to the California budget to help repay CIRM’s bonds. In addition, recognizing that new therapies would take years to develop, the article identified potential shorter-term benefits such as basic science advances leading to the development of new animal models of diseases, novel drug development, new diagnostic tools, and the training of scientists. CIRM has made claims, even in advance of the approval and marketing of successful therapies based on research it supported, that there already has been significant economic benefits to California from its funding (Longaker, Baker, and Greely 2007). This claim appears to be supported by a 2019 report by researchers at the University of Southern California’s Schaeffer’s Center for Health Policy & Economics that was mentioned in Chapter Five. The report looked at the total quantifiable economic impacts of CIRM on the California economy based on the economic stimulus created by CIRM grants, co-funding partnership funding, leverage funding of Alpha Stem Cell Clinics, follow-on funding, and CIRM operational expenditures. According to the report, nearly half of

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these impacts emanate directly from the CIRM grants themselves, which amounted to $2.67 billion at the time the report was written. In addition, an analysis was performed of further funding downstream as commercialization of CIRM research progresses in the form of venture capital, licenses, and contributions to biotechnology clusters in the state (Wei and Rose 2019, ES1-ES2). The report does not include estimates of such benefits as the value of life saved and other direct and indirect health benefits, reduction of medical costs, and a stimulus to the medical research and practice. The total quantified economic impacts of CIRM on the California economy as of 2019 are estimated in the Center for Health Policy & Economics report to be the following, about half of which are concentrated in medical and health related research, manufacturing, and service sectors: x $10.7 billion of additional gross output (sales revenue); x $641.3 million of additional state/local tax revenues and $726.6 million of additional federal tax revenue; x 56,549 additional full-time equivalent jobs, half of which offer salaries above the state average.

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The report estimates the total quantified economic impacts of CIRM on the economy of the rest of the U.S. as the following: x x x x

$4.7 billion of additional gross output; $198.7 million of additional state/local tax revenue; $208.6 million of additional federal tax revenue; 25,816 additional jobs (Wei and Rose 2019, ES1).

The methodology by which these benefits are determined, which are explained in detail in an Appendix to the report, may be open to question, but perhaps more importantly, do these data convincingly show that pluripotent stem cells are a good economic investment? I don’t think so. Very few, if any, states will replicate the size of California’s investment or its educational, research, medical, and manufacturing base. More importantly, should decisions about investments in stem cell research and development be made on the basis of their economic potential? I would argue they should not be. Much of the data cited in the report are likely to accrue to individuals and private companies and not to public benefit. Even the additional state and federal revenue, while helpful, may not necessarily be invested in programs that can improve public welfare. From a justice perspective it seems more appropriate to judge investments in pluripotent

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stem cell research on the basis of how much they are likely to advance public health and well-being.

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Making Pluripotent Stem Cell Therapies Affordable and Accessible Justice requires equitable and affordable access to pluripotent stem cell– based therapies, particularly those publicly funded, but if the cost of gene therapies deyeloped to date is any indication, pluripotent stem cell therapies are likely to be very expensive. Glybera, which in 2012 was the world’s first gene therapy to be approved for marketing, was created to correct a faulty gene response for lipoprotein lipase deficiency. It cost one million dollars for a one-time dose. Though safe and effective, it was a commercial failure due to its high cost and the limited demand generated by such a very rare condition. It was withdrawn in 2017, two years after it went on the market (Baylis 2019, 26). Luxterna, the first gene therapy approved in the U.S., which treats a form of congenital blindness, costs $850,000 ($425,000 per eye) for a one-time treatment (Feuerstein and Garde 2019), and Zolgensma, a gene therapy for pediatric spinal muscular atrophy, is priced at $2.1 million, also for a single treatment, making it the most expensive therapeutic, so far on the market (Stein 2019). Like gene therapy pluripotent stem cell therapies will be expensive to produce, likely require only a single treatment, and many of them not applicable to a sizable number of patients although the number will be larger than any of the gene therapies approved to date. So, what does this mean? François Baylis’ caution about equitable access to the fruits of publicly funded nonheritable genome editing research would apply as well to the fruits of publicly funded pluripotent stem cell research: “If governments that fund such research do not, at the same time, commit to publicly funding the therapies that are developed as a result of the research, then arguably they are using the public purse to subsidize potential future therapies for a privileged few (those who could afford the therapy without public funding). To put it mildly, this is morally questionable.” She goes on to observe, “Moreover, I doubt there would be widespread enthusiasm for human genome editing research if it were clear from the outset that potential therapies would be an exorbitant luxury beyond the reach of most people” (Baylis 2019, 25). I would agree. This then leads to the question of what governments can do to try to make these therapies affordable and widely accessible. Currently no governments have explicitly pledged to underwrite the cost of gene therapy although it can be assumed that countries with publicly funded universal

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health care programs may do so for at least some of the therapies. Nor have any governments made a commitment to do so once stem cell–based therapies are available. I think that using mechanisms to control pricing is therefore central to any effort. Subsidies to help underwrite the costs may also be needed. As described above, CIRM’s intellectual property provisions have required CIRM’s grantees and their exclusive licensees to submit plans to CIRM indicating how they will assure access to any drug resulting from CIRM funded research to Californians who have no other means to purchase the drug. I have criticized this provision as being inadequate because it fails to control the price of the drug or therapy for everyone else in California or more broadly outside of California (Chapman 2018). Even if a Californian had a health care plan willing to pay the likely exorbitant price of such therapies, the insurer’s doing so could raise premiums for everyone in their insurance pool. Moreover, this formula ignores everyone outside of California who might need the therapy but lack insurance that would cover it. This concern is more adequately addressed in the provisions of the proposed 2020 proposition to provide CIRM with a second round of funding. The 2020 initiative proposes to establish a working group, the Treatments and Cures Accessibility and Affordability Working Group, with the following functions: x To work with the Alpha Clinics, the network of clinics CIRM established to conduct clinical trials of cell-based therapies, and other California healthcare institutions and healthcare insurers, government programs, and foundations, to develop model programs and coverage models to promote access to and the affordability of treatments and cures arising from institute-funded research for California patients, regardless of their financial means; x To recommend to the Governing Board of CIRM policies and programs to help Californians afford to participate in human clinical trials and to make treatments and cures arising from institute-funded research affordable to all California patients regardless of their financial means; x To advise the Governing Board regarding the pricing of treatments and cures arising from institute-funded research for patients both through publicly and privately funded programs in California (Klein 2019, 6–7). The proposal also has other provisions related to affordability. It specifies that the Governing Board of CIRM, the Independent Citizen’s

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Oversight Committee (ICOC), will be mandated to establish and oversee the development of policies and programs to help make treatments and cures arising from institute-funded research available and affordable for California patients. To do so, it is to engage with healthcare providers, research and therapy development institutions, businesses, governmental agencies, philanthropists, foundations, and advocacy groups on the implementation of programs to enhance patient access to affordable stem cell and related treatments and cures through public hospitals and clinic (Klein 2019, 17). The intellectual property provisions in the proposal enumerate that recipients of CIRM grants make rather steep royalty payments to CIRM, more or less similar to the current CIRM requirements. The proposed initiative also mandates that the Governing Board establish standards that require that grants and loans awarded be subject to intellectual property agreements that balance the opportunity of the State of California to benefit from the patents, royalties, and licenses that result from the research products, treatments, and cures resulting from CIRM assistance with ensuring that essential medical research would not be hindered. Importantly, the funds so collected are to be placed in an interest bearing account, and to the extent permitted by law, used for the purpose of offsetting the costs of providing treatments from institute funded research to California patients lacking sufficient means to cover the cost of the treatment or cure, including the reimbursement of patient costs for research participants (Klein 2019, 14). So, would these provisions, if instituted, assure affordability? The draft proposition constitutes a commendable and thoughtful effort in that direction, and it certainly goes much farther than any other current proposal to address this significant and complex issue. However, I doubt that these policies would result in affordable therapies and cures because there are no stringent price control measures. Disappointingly the draft of the 2020 initiative does not include a commitment to imposing requirements on recipients of CIRM awards that would link receipt of support from CIRM with the requirement to affordably price the therapies developed with CIRM assistance. Nor is there an explicit requirement for recipients of CIRM funding to abide with the recommendations drafted by the Treatment and Cures Accessibility and Affordability Working Group which would presumably be adopted by the Governing Board. Also, up to now CIRM has received little in the way of royalties from recipients of its grants. Although this is understandable since its grants have yet to result in approved therapies, it is questionable whether the future revenues would be sufficient to close the gap between the costs of the therapy and patients’ resources.

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And there is a lack of concern with the implications of CIRM policies on patients outside of California. Reasonable pricing for patients in California, if achieved, might be at the expense of even higher prices imposed outside of California. Then there is the question of whether or which private insurers will be willing to cover expensive stem cell treatments. Surprisingly, several insurers have been willing to cover Zolgensma gene therapy’s $2.1 million up front cost (Schafer 2020). Part of the incentive may be the existence of a very expensive medical therapy which has high recurrent annual costs. So this willingness to fund Zolgensma will not necessarily carry over to other gene therapies or to pluripotent stem cell therapies once developed. Moreover, the willingness to make these investments may not apply to all insurers, particularly public insurance programs which have been reluctant to underwrite the costs of high-priced therapies like the treatments for hepatitis C that are likely a fraction of the likely cost of future pluripotent stem cell therapies (Chapman and Buckley 2017).

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Final Reflections: Bringing Pluripotent Stem Cell Therapies into Clinical Use It is now a bit more than 20 years since the first derivation of human embryonic stem cells and not quite 15 years since the development of human induced pluripotent stem cells. During this time stem cell scientists have made significant progress in understanding pluripotent stem cell biology and begun to develop potential pluripotent stem cell therapies. More than 40 clinical trials have been initiated to treat a variety of diseases and disorders. The majority are early Phase I or Phase II trials which indicates we are still a long way from them being an approved therapy, but a few are on the threshold of beginning Phase III. Currently very few pluripotent stem cell–based therapies are as yet available in standard clinical practice other than those that are have gone through an expedited and conditional Japanese process of review that does not require a Phase III trial. This book has been critical about the use of fast-tracked processes for a new frontier of science like pluripotent stem cells and also tried to explain why development of these therapies is taking what for many people seems like a very long time. Nevertheless, the lack of these heralded new therapies is a source of distress to many people who have pinned their hopes on pluripotent stem cell–based therapeutics for their currently untreatable conditions. As noted many times in previous chapters, some critics of what they perceive as the slow progress of the field have not taken into account the complexities of translating new potential therapies, particularly therapies in a new field, from the laboratory

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to the bedside. Moreover, is it really taking such a very long time to develop pluripotent stem cell–based therapies? The first clinical trial for a therapy derived from human embryonic stem cells was launched only 12 years after the initial derivation of these cells. Twelve years from an initial discovery of a novel type of cell to a clinical trial with a therapy developed from this type of cell is an extraordinarily short period of time, perhaps too short. In contrast, the first efforts to develop a human gene therapy began in 1980 and the first human trials in 1990, but it was not until 2012 that Glybera was approved for clinical applications in the European Union for pancreatic disorders and 2017 when the FDA approved two gene therapies, Kymriah for leukemia and Luxturna to treat an inherited form of vision loss. Therefore, for those disappointed with the rate of progress one response might be that they hold unrealistic expectations. Analysts of the field have also pointed to other factors as to why regenerative stem cell medicine or specifically pluripotent stem cell research has yet to offer new treatments. Much of Chapter Four was taken up with a discussion of these impediments. Those noted include the following factors. Regulatory frameworks have been slow to develop and are still evolving especially for the clinical application of stem cell products. The FDA, for example, did not set out clear-cut review criteria from the start for the Investigational New Drug application process but instead initiated a series of long, drawn-out negotiations that included the development of new assessment parameters. Regulatory requirements also became more stringent in the UK. It has often been difficult to raise sufficient funds particularly for clinical trials. Stem cell–based therapies are moving into clinical trials in a highly challenging funding environment. Industry is reluctant to invest until there are further demonstrations of success for therapeutic applications. Another complication is the difficulty of recruiting sufficient numbers of patients for the clinical trials, especially for the diseases and disorders with relatively low prevalence rates. Also, in contrast with candidate medicines where there are well-functioning research and review platforms, there is not an established clinical trials infrastructure for pluripotent stem cell research (Rosemann 2014). Perhaps most importantly, the impact of public controversies about the use of human embryonic stem cells has slowed down the development of the field. One of the themes in this book has been that the derivation and use of human embryonic stem cells is ethically permissible if done with appropriate scientific and ethical oversight. Also, the perspective put forward is that therapies developed from human embryonic stem cells are both more promising and safer than induced pluripotent stem cells.

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Therefore I agree with the statement of Jonathan Poulos cited in Chapter Two that by sidelining human embryonic stem cells on the basis of moral objections the regenerative potential of stem cells is left unfulfilled (Poulos 2018, 21). Or it can at least be said it is slowed down. Nevertheless, I am optimistic that therapies developed from pluripotent stem cells will be forthcoming. Neither I nor anyone else can identify which therapies and when they will be available. However, as indicated in Chapter Six, much of the focus of the initial human pluripotent stem cell clinical trials has been on ophthalmic indications. As explained there, the eye constitutes an accessible and relatively immune-privileged site which means it has an ability to tolerate non-histocompatible cells without eliciting an immune response. Also, the subretinal space in the eye is protected by the blood–ocular barrier (Schwartz et al. 2012). The eye is also accessible for injection or surgery, and it can be noninvasively monitored by visualization through the lens after injection of the therapy (Kimbrel and Lanza 2015). Several of the trials currently underway are showing promising results, suggesting that macular degeneration may be the first disorder with a pluripotent stem cell–based therapy approved for marketing in the U.S. and Europe. So, to quote the headline of a 2017 newspaper article based on an interview with Shinya Yamanaka, “the stem-cell revolution is coming – slowly” (Ravven 2017). I think the wait will be found to be worthwhile.

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