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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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1

Introduction

Genome editing1 is a powerful new tool for making precise additions, deletions, and alterations to the genome—an organism’s complete set of genetic material. The development of new approaches—involving the use of meganucleases; zinc finger nucleases (ZFNs); transcription activator-like effector nucleases (TALENs); and, most recently, the CRISPR/Cas9 system—has made editing of the genome much more precise, efficient, flexible, and less expensive relative to previous strategies. With these advances has come an explosion of interest in the possible applications of genome editing, both in conducting fundamental research and potentially in promoting human health through the treatment or prevention of disease and disability. The latter possibilities range from editing somatic cells to restore normal function in diseased organs to editing the human germline to prevent genetic diseases in future children and their descendants.

As with other medical advances, each application comes with its own set of benefits, risks, regulatory questions, ethical issues, and societal implications. Important questions raised with respect to genome editing include how to balance potential benefits against the risk of unintended harms; how to govern the use of these technologies; how to incorporate societal values into salient clinical and policy considerations; and how to respect the in-

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1 The term “genome editing” is used throughout this report to refer to the processes by which the genome sequence is changed by adding, replacing, or removing DNA base pairs. This term is used in lieu of “gene editing” because it is more accurate, as the editing could be targeted to sequences that are not part of genes themselves, such as areas that regulate gene expression.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

evitable differences, rooted in national cultures, that will shape perspectives on whether and how to use these technologies.

Recognizing both the promise and concerns related to human genome editing, the National Academy of Sciences (NAS) and the National Academy of Medicine (NAM)2 convened the Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations to carry out the study that is documented in this report. While genome editing has potential applications for use in agriculture and nonhuman animals,3 this committee’s task (see Box 1-1) was focused on human applications.4 The charge to the committee included elements pertaining to the state of the science in genome editing, possible clinical applications of these technologies, potential risks and benefits, whether standards can be established for quantifying unintended effects, whether current regulatory frameworks provide adequate oversight, and what overarching principles should guide the regulation of genome editing in humans.

STUDY CONTEXT

The NAS and the NAM Human Gene-Editing Initiative

In light of the promise of genome editing and the associated regulatory and ethical issues, the NAS and the NAM established an initiative to explore these issues in greater depth and facilitate U.S. and international dialogue on how to address them. The first activity of this Human Gene-Editing Initiative was the convening of the International Summit on Human

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2 The NAS and the NAM are referred to throughout this report simply as the National Academies, or the U.S. National Academies when discussed in relation to the academies of other nations. Until 2016, the NAM was known as the Institute of Medicine (IOM).

3 In January 2017, the U.S. Food and Drug Administration (FDA) issued revised draft guidance addressing the regulatory pathway for intentionally altered genomic DNA in plants and nonhuman animals. This would include DNA intentionally altered through genome editing. The guidance does not affect the regulatory pathway for human applications that are regulated as human drugs, devices, and biologics. See FDA “Regulation of Intentionally Altered Genomic DNA in Animals—Draft Guidance” (January 2017) at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm113903.pdf (accessed January 30, 2017) and “Genome Editing in New Plant Varieties Used for Foods; Request for Comments” at https://www.regulations.gov/document?D=FDA-2016-N-4389-0001 (accessed January 30, 2017).

4 The regulatory roles of the federal departments and agencies and the overall framework for regulation of applications of biotechnology are outlined in “Modernizing the Regulatory System for Biotechnology Products: Final Version of the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology” (January 4, 2017) and “National Strategy for Modernizing the Regulatory System for Biotechnology Products” (September 2016) (https://obamawhitehouse.archives.gov/blog/2017/01/04/increasing-transparency-coordination-andpredictability-biotechnology-regulatory [accessed January 30, 2017]).

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

Gene Editing: A Global Discussion jointly with the Chinese Academy of Sciences and The Royal Society of the United Kingdom. This 3-day event addressed a number of scientific advances in the development of modern genome-editing tools, potential medical uses of these tools in human pa-

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

tients, and ethical and social issues their uses might pose. The organizing committee released a statement that summarized its conclusions from the meeting (NASEM, 2016d). Panel chair David Baltimore also noted “we hope that our discussion here will serve as a foundation for a meaningful and ongoing global dialogue” (NASEM, 2016d, p. 6). All three nations embraced the statement’s call for continued research on gene editing, further deliberation with regard to heritable changes, and a continued public discourse on the topic.5 The summit provided important input to the present study, as did other studies by the NAS and the NAM on related topics (see Box 1-2).

This committee was convened to continue the dialogue initiated by the International Summit and to undertake a year-long, in-depth consensus study. As specified in its statement of task (see Box 1-1), the committee examined the state of the science in human genome editing, its potential applications, and the ethical issues that need to be considered in deciding how to govern the use of these powerful new tools. This report is the product of that study and, as with all other National Academies consensus studies, underwent peer review by an independent panel of experts. Additional activities of the Chinese Academy of Sciences and The Royal Society of the United Kingdom are anticipated, including another international summit to take place in China in 2018.

BACKGROUND

U.S. and International Policy Discussions

Among the earliest calls for a detailed examination of the implications of genome-editing technologies were those made by members of the scientific community engaged in developing these tools and advancing their clinical applications. In 2015 a group of investigators and ethicists, including CRISPR/Cas9 developers, met in Napa, California, and subsequently published a request for the community to explore the nature of human genome editing and provide guidance on its acceptable uses (Baltimore et al., 2015). That same year, a number of articles and commentaries appearing in scientific journals and the popular press called attention to scientific and ethical challenges that would be posed by CRISPR/Cas9 and similar

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5 Statement by Ralph J. Cicerone, President, U.S. National Academy of Sciences; Victor J. Dzau, President, U.S. National Academy of Medicine; Chunli Bai, President, Chinese Academy of Sciences; and Venki Ramakrishnan, President, The Royal Society (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015b [accessed January 24, 2017]).

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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genetic tools (Bosley et al., 2015; Editing Humanity, 2015; Lanphier et al., 2015; Maxmen, 2015; Specter, 2015).

Professional bodies, international organizations, and national academies of sciences and medicine further raised the profile of genome editing by issuing statements on its appropriate uses, particularly in reference to the potential for creating heritable genetic modifications. Among others, they included the U.K. Academy of Medical Sciences and a number of collaborative partners; the European Group on Ethics in Science and New Technologies, an advisory body to the president of the European Commission; the Council of Europe; and the International Society for Stem Cell Research (AMS et al., 2015; Council of Europe, 2015; EGE, 2016; Friedmann et al., 2015; Hinxton Group, 2015; ISSCR, 2015). The United Nations Educational, Scientific, and Cultural Organization (UNESCO) (2015) issued updated guidance to reflect genome-editing advances. Others launched activities to examine the implications of genome editing in greater detail, including the Académie Nationale de Médecine (France) (ANM, 2016); Institut Nationale de la Santé et de la Récherche Médicale (France) (INSERM; Hirsch et al., 2017); Berlin-Brandenburg Academy of Sciences and Humanities (BBAW, 2015); National Academy of Sciences Leopoldina, in partnership with the Deutsche Akademie der Technikwissenshaften (National Academy of Science and Engineering: “acatech”), Deutsche Forschungsgemeinschaft (German Research Foundation: DFG), and Union der deutschen Akademien der Wissenschaften (Union of German Academies of Sciences and Humanities: Academien Union) (National Academy of Sciences Leopoldina et al., 2015); Federation of European Academies of Medicine (FEAM, UKAMS, and ANM, 2017); Royal Netherlands Academy of Arts and Sciences (KNAW, 2016); Nuffield Council on Bioethics (Nuffield Council, 2016b); and others (see Box 1-3).

The Technologies

New or improved tools facilitate scientific progress by making it possible to investigate new kinds of questions and to generate new solutions. In the area of health and medicine, scientists and clinicians have long sought to apply the techniques of molecular biology to understand basic biology—including embryonic development, physiology, and the immune and nervous systems—and to treat or prevent disease. Much progress has been made in elucidating the role of genetics in diseases, ranging from sickle-cell anemia, muscular dystrophy, and cystic fibrosis, to such conditions as deafness, short stature, and blindness. The development of many such diseases and conditions has a genetic component. Some result from straightforward single-gene changes, but most involve a complex interplay of genetic, environmental, and other factors that remain only imperfectly

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

understood. Furthermore, genetic sequences themselves paint only part of the biological picture. Regulation of how and when genes are turned on and off, including the role of the epigenome,6 continues to be actively explored. Controlled gene expression and epigenetic alterations influence how tissues develop and differentiate and have clinical ramifications in such areas as cancer and embryonic development.

Tools that enable investigators to alter DNA sequences in order to understand or improve their function are not new. Recent years, however, have seen the development of a suite of genome-editing tools that allow for easier, better controlled, and more accurate changes to DNA inside cells. These tools are based on exogenous enzymes that cut DNA at specific locations, combined with endogenous processes that repair the broken DNA, thereby enabling letters of the genetic code to be added, modified, or deleted. The speed with which this technology has been adopted in research laboratories and further adapted to tackle additional scientific challenges is a reflection of how powerful a technique the editing of genes and genomes will be for the scientific and clinical communities.

The earliest applications of nuclease-based genome-editing methods employed targeted recognition of specific DNA sequences by proteins: homing nucleases (also known as meganucleases), ZFNs, and TALENs. However, the recent development of RNA-based targeting has greatly simplified the process of genome editing. The first publications on the subject, in 2012-2013, explained how the CRISPR/Cas9 system, derived from a natural bacterial defense mechanism against infecting viruses, can be harnessed to make controlled genetic changes in any DNA, including that of human cells (Cho et al., 2013; Cong et al., 2013; Jinek et al., 2012, 2013; Mali et al., 2013). This was a game-changing advance. These methods have rapidly been adopted by scientists worldwide and have greatly accelerated fundamental research that has included altering cells in the laboratory to study the functions of particular genes, developing models for studies of human diseases using stem cells or laboratory animals, creating modified plants and animals to improve food production, and developing therapeutic uses in humans. Genome editing has rapidly become an invaluable core technology in research laboratories and biotechnology companies, and is already moving into clinical trials (e.g., Cyranoski, 2016; Reardon, 2016; Urnov et al., 2010).

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6 The term “epigenome” refers to a set of chemical modifications to the DNA of the genome and to proteins and RNAs that bind to DNA in the chromosomes to affect whether and how genes are expressed.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

The Issues

Individual-Level Concerns

As with other types of medical interventions, whether genome editing can be used in patients will depend largely on understanding the safety and efficacy of the treatment and evaluating whether the anticipated benefits are reasonable with respect to the risk of adverse effects. Treatments based on genome editing are intended to make controlled modifications to specific portions of the DNA that affect the functions of their target(s) while avoiding changes to other portions whose alteration is not desired. The latter alterations, referred to as off-target events, could have consequences, many unnoticeable but others damaging, depending on their location and their effects. In general, human genome editing raises questions common to the process of researching and developing new treatments: which conditions or diseases are most suitable to address with these technologies, how to identify and evaluate off-target events and other potential side effects, and which patients are most appropriate for studies. As described in this report, regulatory systems for addressing the individual-level concerns associated with genome editing already exist in the United States and many other countries, but can be improved.

Societal-Level Concerns

The use of genome editing also has significant social dimensions that vary depending on the proposed application. The use of a genome-editing treatment whose effects are nonheritable and are restricted to an individual patient may not differ greatly from the use of a traditional drug or medical device. By contrast, making changes that may be inherited by future generations raises questions about the extent to which the long-term effects of proposed edits can be predicted and whether it is appropriate for humans to purposely alter any aspect of their genetic future (Frankel and Chapman, 2000; Juengst, 1991; Parens, 1995). In addition, identifying the increased range of applications made possible by genome editing may be yet another challenge to conventional conceptions of what constitutes a disease or disability. Societal-level concerns are particularly acute with respect to genome-editing interventions aimed at enhancing human capabilities. Such applications also raise questions about how to define and promote fairness and equity (President’s Council on Bioethics, 2003). Moreover, as with other genetic technologies, such genome-editing applications may raise concerns about coercive and abusive eugenics programs of the past, which were based on faulty science and served discriminatory political goals (Wailoo et al., 2012).

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

Looking Beyond Safety and Efficacy

Although the nature of the debate surrounding genome editing is not new, the tools available in the past for making genetic modifications in human cells were time-consuming, difficult, and expensive, and were unlikely to be used outside of specialized medical applications. Recent genome-editing technologies, particularly the CRISPR/Cas9 system, have greatly expanded the landscape of potential applications and potential users. Their rapid development and adoption also have shortened the timeline for discussion of what appropriate governance structures need to be identified or developed. As the safety and efficacy of these technologies continue to improve, the critical question will become not whether scientists and clinicians can use genome editing to make a certain change, but whether they should. There is already discussion of do-it-yourself (DIY) editing and the use of genome-editing tools by the biohacker and DIY biology communities, albeit in nonhuman organisms (Brown, 2016; Ledford, 2015). Thorny issues around acceptable uses of the technology in humans will depend on more than scientific considerations, and may increasingly involve weighing factors beyond individual-level risks and benefits (NRC, 1996).

Layered on the scientific and ethical issues associated with human genome editing is the question of how to govern its application so as to facilitate its appropriate use and avoid its misuse. Determining the limits of the technologies’ uses and the regulatory mechanisms needed to enforce these limits will vary according to each nation’s cultural, political, and legal context. But whether and how best to move human genome editing forward has implications for transnational scientific cooperation that require ongoing public discussion and input into policy making. There is ample precedent for scientists and other stakeholders to engage in just such activities, and this report is intended to build on points raised by a number of international conventions and declarations, such as the Oviedo Convention (1997), the International Declaration on Human Genetic Data (2003), and the Universal Declaration on Bioethics and Human Rights (2005) (Andorno, 2005a,b; UNESCO, 2004a, 2005).

STUDY APPROACH

To address its complex task (see Box 1-1), the committee included members with expertise in basic and clinical research, in the development of human genetic therapies, and in U.S. and international legal and regulatory frameworks. It included biologists, bioethicists, and social scientists, and incorporated perspectives from potentially affected patient and stakeholder communities. Because the ethical and social issues posed by human genome editing transcend national boundaries, the committee included not only

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

U.S. members but also those who are citizens of or are currently working in Canada, China, Egypt, France, Germany, Israel, Italy, Spain, and the United Kingdom. Brief biographies of the committee members are found in Appendix D.

This study was informed not only by the International Summit described earlier, which immediately preceded the committee’s first meeting, but also by review of the salient literature, additional meetings, and speakers who generously shared their knowledge with the committee. Further information on the process by which the committee conducted this study is provided in Appendix C.

In evaluating the implications of new genome-editing tools, the committee also reviewed scientific progress, ethical debates, and regulatory structures related to the use in humans of medical developments such as assisted reproductive technologies, stem cell therapies, gene transfer, and mitochondrial replacement techniques. These developments interface with those of genome editing because editing of stem cells has potential clinical applications for treating or preventing disease, and reproductive technologies would have to be used in combination with genome editing for any heritable application of the latter technologies. As these other technologies have advanced, legal and regulatory frameworks and ethical norms of conduct have been developed to provide guidance on their appropriate human uses and oversight (Health Canada, 2016; HFEA, 2014; IOM, 2005; NASEM, 2016e; NRC and IOM, 2007, 2008; Nuffield Council, 2016a; Präg and Mills, 2015; Qiao and Feng, 2014). The reports cited here helped provide a basis for the committee’s assessment of the use of genome-editing tools in humans and are referenced in subsequent chapters where relevant.

ORGANIZATION OF THE REPORT

The report begins by reviewing international norms that are embodied in the set of overarching principles adopted by the committee for governance of human genome editing (Chapter 2). The chapter continues with an overview of the U.S. regulation of research and clinical application of genome editing, drawing comparisons where appropriate to other national systems of oversight.

With this grounding in principles and regulation, Chapters 3-6 delve into human genome-editing technology and the scientific issues, regulatory context, and ethical implications of four specific applications. Laboratory research conducted in somatic cells and nonheritable laboratory research in human germ cells, gametes, or early-stage embryos is covered in Chapter 3. Chapter 4 examines the uses of genome editing for somatic interventions focused on therapy, including fetal therapy. Chapter 5 addresses the use

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
×

of genome-editing technology in germline cells for potential research and clinical therapeutic applications in human patients. Chapter 6 considers the potential use of human genome editing to enhance human functions rather than to treat or prevent disease or disability.

The subsequent chapter (Chapter 7) turns from analysis of these categories of application to the role of public input in determining how genome-editing technology should be governed in the future, both in the United States and in other countries. The chapter considers public engagement for different categories of genome-editing applications and explores strengths and limitations of potential models for undertaking such public engagement.

Finally, Chapter 8 returns to the set of overarching principles and the responsibilities that flow from them in the context of human genome editing. The chapter pulls together the report’s conclusions and recommendations in light of these fundamental concepts.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/24623.
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Genome editing is a powerful new tool for making precise alterations to an organism’s genetic material. Recent scientific advances have made genome editing more efficient, precise, and flexible than ever before. These advances have spurred an explosion of interest from around the globe in the possible ways in which genome editing can improve human health. The speed at which these technologies are being developed and applied has led many policymakers and stakeholders to express concern about whether appropriate systems are in place to govern these technologies and how and when the public should be engaged in these decisions.

Human Genome Editing considers important questions about the human application of genome editing including: balancing potential benefits with unintended risks, governing the use of genome editing, incorporating societal values into clinical applications and policy decisions, and respecting the inevitable differences across nations and cultures that will shape how and whether to use these new technologies. This report proposes criteria for heritable germline editing, provides conclusions on the crucial need for public education and engagement, and presents 7 general principles for the governance of human genome editing.

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