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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
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1

Introduction

Mitochondrial replacement techniques (MRT) are novel procedures designed to prevent the maternal transmission of mitochondrial DNA (mtDNA) diseases. Such diseases are rare, yet can be severely debilitating, progressive, and often fatal in infancy or childhood. While MRT could provide a reproductive option for women at risk of passing on mtDNA disease to their children, it raises a series of complex ethical and social questions that have implications for public policy.

STUDY BACKGROUND AND CONTEXT

Origin of the Study

On February 25-26, 2014, the U.S. Food and Drug Administration (FDA) convened a meeting of its Cellular, Tissue and Gene Therapies (CTGT) Advisory Committee to discuss “oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility” (FDA Cellular Tissue and Gene Therapies Advisory Committee, 2014). The oral comments received by FDA from members of the public at this meeting revealed substantial concern among certain commenters about the perceived ethical, social, and policy implications of the proposed techniques, which entailed issues outside the scope of the advisory committee’s discussion. In response, FDA requested that the Institute of Medicine produce a consensus report addressing these issues and how they might influence the conduct of clinical investigations for MRT; the charge to the committee is presented in Box 1-1. FDA indicated that

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

BOX 1-1
Charge to the Committee

Ad hoc committee of the Institute of Medicine will conduct a study to develop a report that will inform the U.S. Food and Drug Administration in consideration of review of applications in the area of genetic modification of eggs and zygotes for the prevention of mitochondrial disease specific to mitochondrial DNA. These include maternal spindle transfer, pronuclear transfer, and polar body transfer but could also encompass other technologies not currently proposed.

The development of novel techniques in this area raises complex ethical and social policy issues, including

  • Whether manipulation of mitochondrial content should be considered germline modification (defined as human inheritable genetic modification) in the same way and with the same social and ethical implications as germline modification of nuclear DNA, or whether, from a social and ethical perspective, it should be viewed differently from germline modification of nuclear DNA.
  • The implications of manipulating mitochondrial content both in children born to women as a result of participating in these studies and in descendants of any female children.
  • Ethical issues in providing “consent” or “permission” to accept risks on behalf of a child who does not exist.
  • Ethical and social issues that arise if a child is born with genetic material from three individuals.

it will take the recommendations of this report into consideration in its review of future Investigational New Drug (IND) applications for clinical investigations of MRT.

mtDNA Disease

Mitochondria are microscopic organelles present in almost every cell type of the human body. Although they are now recognized as having myriad functions, their main role is the production of cellular energy through a process termed oxidative phosphorylation. The majority of a cell’s genes and DNA are housed in its nucleus; the mitochondria contain only 37 genes, all of which encode for molecules essential to oxidative phosphorylation.

Diseases that affect the mitochondria can be caused in three ways: an individual inherits a pathogenic mtDNA mutation from its mother; an in-

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

Taking into consideration these ethical and social policy issues, the committee’s report will address the conduct of clinical investigations of these novel techniques, including the foundational question of whether safeguards such as specific measures and public oversight could adequately address the social and ethical concerns, or whether those concerns preclude clinical investigations. In addition, the report will specifically examine:

  • The circumstances under which clinical investigations of the technology for the prevention of mitochondrial disease might be conducted ethically, including implications for the concept of “informed consent” and other aspects of the enrollment and tracking of participants during and after the trial.
  • Whether, and how, the existence of alternative approaches to prevent the transfer of mitochondrial disease from mother to child (e.g., adoption, egg donation, or preimplantation genetic diagnosis for mitochondrial mutations for which it would be informative) should factor into the assessment of allowing these trials to proceed.
  • Whether it is advisable to establish controls that would distinguish between genetic modification to prevent transmission of mitochondrial disease (therapeutic/prevention purposes) and genetic modification to enhance desired traits (enhancement purposes). What controls could be effective at maintaining this distinction, particularly for first-in-human clinical investigations?

dividual inherits a pathogenic nuclear DNA (nDNA) mutation from one or both parents that affects mitochondrial function; or an individual develops a de novo pathogenic mutation in either mtDNA or nDNA that affects mitochondrial function. MRT focuses only on the first type of causation—maternal transmission of pathogenic mtDNA mutations. During the process of sexual reproduction, the father’s mtDNA is destroyed; only the mother’s mtDNA is passed on to the child.1 If a mother is homoplasmic for a pathogenic mutation (all of her mtDNA has the same mutation), all of her offspring will have the mutation. If a mother is heteroplasmic (some mtDNA is normal and some is mutated), her offspring will have varying levels of mutated, pathogenic mtDNA. The proportion of mutated, pathogenic

_________________

1 There has been one reported case of paternal transmission of mtDNA in humans, but the vast majority of evidence points to sole maternal transmission. See, e.g., Filosto et al. (2003); Schwartz and Vissing (2002); and Taylor et al. (2003).

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

mtDNA may have clinical significance, with more severe disease generally being associated with a higher percentage of mutated, pathogenic mtDNA.

Given the complexity of mitochondrial biology, mtDNA diseases can vary markedly from patient to patient; however, they are often debilitating, progressive, and fatal at a young age. Common symptoms of mtDNA disease include muscle weakness, extreme fatigue, seizures, developmental delays, heart problems, and gastrointestinal disorders. Diagnosis can be complicated, as these diseases often share symptoms with other disorders, and testing requires an integrated approach that could include metabolic, muscle, and genetic tests. The prevalence of disease-causing mtDNA mutations is difficult to estimate, but an epidemiological survey in the North East of England suggests a minimum point prevalence of 1 in 5,000 (Gorman et al., 2015).

Mitochondrial Replacement Techniques

MRT is an in vitro fertilization (IVF) technique that involves removing an intended mother’s nDNA from her oocyte or zygote, which contains mutated mtDNA, and transferring it into a female provider’s oocyte or zygote, which contains nonpathogenic mtDNA and from which the nDNA has been removed.2 The woman providing oocytes would have no personal or family history or genetic evidence of having mutated, pathogenic mtDNA. In this report, the term “MRT” encompasses both the transfer of the nuclear genetic material and the accompanying fertilization procedure that is necessary to produce a human embryo. These techniques could allow intended mothers to produce a child that would share their nDNA without passing on their pathogenic mtDNA. Three such techniques are most advanced in development: maternal spindle transfer (MST); pronuclear transfer (PNT); and, most recent, polar body transfer (PBT). (See Chapter 2 for more detailed description of these techniques.)

Maternal Spindle Transfer (MST)

In this technique, the nuclear chromosomes, which are grouped in a spindle formation, would be removed from both an oocyte provided by a woman with nonpathogenic mtDNA and the intended mother’s oocyte. The intended mother’s oocyte, containing mutated mtDNA, would be discarded. The intended mother’s nuclear chromosomes would be inserted

_________________

2 This report adopts the framing convention that the intended mother’s pathogenic mtDNA is replaced with nonpathogenic mtDNA from an individual who provides an oocyte and thus constitutes “mitochondrial replacement.” A proposed alternative framing is that the technique is a form of “nuclear transfer.” This report does not contest that, procedurally, nuclear genetic material is moved; rather, the framing adopted emphasizes that mtDNA, rather than nDNA, is being weighted and selected for.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

into the provided oocyte, which would contain nonpathogenic mtDNA. The oocyte would then be fertilized with the intended father’s or another man’s sperm. Following fertilization, the embryo would be grown in culture and subjected to diagnostic testing to ensure its quality and viability; the testing would include preimplantation genetic diagnosis (PGD) to confirm that the embryo had acceptably low or undetectable levels of the pathogenic mtDNA molecules. The resulting embryo(s) would be frozen until test results confirmed suitability for transfer and then transferred into the uterus of the intended mother (or gestational carrier, if needed).

Pronuclear Transfer (PNT)

In this technique, both an oocyte provided by a woman with nonpathogenic mtDNA and the intended mother’s oocyte would be fertilized with sperm in vitro, creating two zygotes. The maternal and paternal pronuclei, which contained the nDNA, would be removed from both zygotes. The intended mother’s enucleated zygote, containing pathogenic mtDNA, would be discarded. The pronuclei from the intended mother’s zygote would be inserted into the enucleated zygote created with the provided oocyte and the intended father’s (or another man’s) sperm, which would contain nonpathogenic mtDNA. The resulting embryo(s) would then be grown, tested, and transferred as detailed above for MST.

Polar Body Transfer (PBT)

There are two versions of PBT. In polar body 1 transfer (PB1T), the intended mother’s first polar body, which is a by-product of oogenesis, containing her nDNA and very little mtDNA, would be transferred to an oocyte provided by a woman with nonpathogenic mtDNA from which the nDNA had been removed. The reconstructed oocyte would then be fertilized, grown, tested, and transferred as detailed above for MST. In polar body 2 transfer (PB2T), both the intended mother’s oocyte and an oocyte provided by a woman with nonpathogenic mtDNA would be fertilized. The intended mother’s second polar body, containing nDNA and very little mtDNA, would be transferred to the zygote of the woman who provided the oocyte, from which the pronuclei had been removed. The resulting embryo(s) would then be grown, tested, and transferred as detailed above for MST.

Other Techniques and Developments

In addition to MST, PNT, and PBT, there are other current and potential future techniques designed to prevent transmission of mtDNA disease.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

PGD is a technique performed in the setting of IVF to test genetically for a known inherited genetic disease and to allow selection of embryos for transfer to the uterus of the woman who will carry the pregnancy, with the goal of establishing a viable pregnancy and preventing transmission of that disease. While PGD is a powerful technique for preventing transmission of nuclear genetic diseases, there are limitations as to its reliability in effectively preventing the transmission of mtDNA disease in some at-risk females. The potential uses and limitations of PGD for preventing transmission of mtDNA disease are discussed in Chapter 2.

Heteroplasmy shift is an investigational technique that selectively targets and degrades mtDNA containing pathogenic mutations, allowing for repopulation of affected cells with resident, nonpathogenic mtDNA. It has recently has been shown to effectively reduce heteroplasmy levels and prevent transmission of pathogenic mtDNA in mouse and mammalian oocytes and one-cell embryos. As a result, heteroplasmy shift has been proposed as an alternative to MRT for preventing maternal transmission of pathogenic mtDNA mutations that precludes the need for the contribution of a second woman’s genetic material (Reddy et al., 2015). Unlike MRT, however, heteroplasmy shift would not be applicable for oocytes or embryos that were homoplasmic or had high heteroplasmy levels for a pathogenic mtDNA, because retaining a certain baseline level of nonpathogenic mtDNA molecules in the cell is essential to enabling repopulation of the mtDNA pool and normal mitochondrial function after degradation of pathogenic mtDNA.

Policy Landscape

As the primary regulatory authority in this area, FDA will decide whether MRT can move forward into clinical investigations, and perhaps eventually into clinical use. While FDA does not have jurisdiction over the practice of medicine in general, it can regulate certain treatments or procedures, including the use of “human cells or tissues that are intended for implantation . . . into a human” (21 CFR 1271). FDA considers standard assisted reproductive technology (ART) procedures such as IVF to be “minimal manipulation” and thus subject only to regulations aimed at the prevention of communicable disease (FDA, 2009). However, FDA considers procedures such as MST, PNT, and PBT that entail “human cells used in therapy involving the transfer of genetic material” to be more than “minimal manipulation,” and thus subject to regulation as drugs and/or biologics (FDA, 2009). In 2001, FDA advised researchers that such use of cells would require an IND, which is the first step toward clinical investigations and requires the submission of preclinical data and information on product safety, details about the technique, and proposed clinical investigation protocols.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

In addition to FDA oversight, MRT research is subject to the limitations of the federal Dickey-Wicker amendment. Dickey-Wicker, included each year as a rider on the U.S. Department of Health and Human Services (HHS) appropriation bill, prohibits the use of HHS funding for research in which embryos are created for research purposes or destroyed, discarded, or subjected to risks with no prospect of medical benefit for the embryo. However, Dickey-Wicker prohibits the use of HHS funding, not the research itself, so MRT research could still be carried out with private funds, provided the technique was not prohibited or otherwise regulated by state law.

In addition, the U.S. National Academy of Sciences and the U.S. National Academy of Medicine have announced an initiative to guide decision making on gene-editing technologies. A 3-day international summit was held in December 2015, in collaboration with the Chinese Academy of Sciences and the United Kingdom’s Royal Society, and an Academies consensus study has been launched to examine the scientific underpinnings of human gene-editing technologies—including potential human germline editing—and the clinical, ethical, legal, and social implications. This new Academies’ effort will consider issues related to gene editing more broadly speaking, encompassing gene-editing techniques targeting nDNA and not limited to MRT or mtDNA. The consensus report of the committee conducting that study, to be released in 2016, will include findings and recommendations on the responsible use of human gene-editing research.3

Outside of the United States, the United Kingdom approved regulations to permit MRT in early 2015. The first preclinical research license for PNT was granted in the United Kingdom in 2005, and in the ensuing years, the United Kingdom’s Human Fertilisation and Embryology Authority (HFEA) conducted extensive reviews of the preclinical evidence and solicited public opinion on MRT. The HFEA performed three scientific reviews to examine the safety and efficacy of MRT, looking at specific techniques and such alternatives as PGD. The HFEA’s Ethics and Law Advisory Committee considered the ethical issues surrounding MRT, and the HFEA consulted and engaged in dialogue with the public through public workshops, surveys, and focus groups. In early 2014, the UK Department of Health released draft regulations for public review, and in early 2015, Parliament considered and approved revised regulations. These regulations require that MRT practitioners obtain a license from the HFEA, which will consider the specific context and techniques proposed for each license. As of late 2015, the United Kingdom was the first and only country in the world to have approved regulations to permit MRT.

_________________

3 For more information, visit http://www.nationalacademies.org/gene-editing.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

STUDY APPROACH

To address the study charge (see Box 1-1), the National Academies of Sciences, Engineering, and Medicine formed an ad hoc committee composed of experts from a range of disciplines, including bioethics, philosophy, law, public policy, religion, clinical investigations, reproductive medicine, mitochondrial medicine, mitochondrial biology, and patient advocacy. The committee deliberated from January to September 2015, holding five 2-day meetings, one 2-day public workshop, and public comment sessions. The committee also solicited and considered written statements from stakeholders and members of the public; in total, the committee received 32 comments submitted via the study website.

To the extent possible, the committee gathered empirical evidence by means of systematic literature reviews to inform its consideration of the ethical, social, and policy issues it was tasked with addressing. In areas in which empirical evidence is not available, however, many of the conclusions and recommendations offered in this report are based on the committee’s expertise and informed judgment. To supplement its own expertise, the committee invited input from experts in the fields of mitochondrial and evolutionary biology, the ethics of reproductive and genetic technologies, and religious studies, as well as mtDNA patients through its public workshop and opportunities for public comment (see Appendix A).

ORGANIZATION OF THE REPORT

The remainder of this report is organized into three chapters. Chapter 2, “Science and Policy Context,” presents an overview of reproductive medicine, mitochondrial biology, and mtDNA diseases; a review of the MRT research conducted to date; and discussion of the potential risks associated with MRT, as well as the policy context surrounding potential human clinical investigations in and clinical applications of MRT. Chapter 3, “Do Ethical, Social, and Policy Considerations Preclude MRT?,” presents the results of the committee’s deliberations and its findings on such issues as heritable genetic modification, implications for identity and parenthood, potential social effects, downstream implications, and alternatives to MRT. Chapter 4, “Regulation and Oversight of MRT in Humans,” presents the committee’s recommendations for key principles to guide clinical investigations of MRT, taking into consideration benefits and risks, informed consent, and practical challenges.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

REFERENCES

FDA (U.S. Food and Drug Administration). 2009. FDA regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) product list. http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm150485.htm (accessed June 19, 2015).

FDA Cellular Tissue and Gene Therapies Advisory Committee. 2014. Oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility. FDA briefing document. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/CellularTissueandGeneTherapiesAdvisoryCommittee/UCM385461.pdf (accessed December 23, 2015).

Filosto, M., M. Mancuso, C. Vives-Bauza, M. R. Vila, S. Shanske, M. Hirano, A. L. Andreu, and S. DiMauro. 2003. Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Annals of Neurology 54(4):524-526.

Gorman, G. S., A. M. Schaefer, Y. Ng, N. Gomez, E. L. Blakely, C. L. Alston, C. Feeney, R. Horvath, P. Yu-Wai-Man, P. F. Chinnery, R. W. Taylor, D. M. Turnbull, and R. McFarland. 2015. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Annals of Neurology 77(5):753-759.

Reddy, P., A. Ocampo, K. Suzuki, J. Luo, S. R. Bacman, S. L. Williams, A. Sugawara, D. Okamura, Y. Tsunekawa, J. Wu, D. Lam, X. Xiong, N. Montserrat, C. Rodriguez Esteban, G. Liu, I. Sancho-Martinez, D. Manau, S. Civico, F. Cardellach, M. del Mar O’Callaghan, J. Campistol, H. Zhao, J. M. Campistol, C. T. Moraes, and J. C. Izpisua Belmonte. 2015. Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161(3):459-469.

Schwartz, M., and J. Vissing. 2002. Paternal inheritance of mitochondrial DNA. New England Journal of Medicine 347(8):576-580.

Taylor, R. W., M. T. McDonnell, E. L. Blakely, P. F. Chinnery, G. A. Taylor, N. Howell, M. Zeviani, E. Briem, F. Carrara, and D. M. Turnbull. 2003. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Annals of Neurology 54(4):521-524.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 19
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 20
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 21
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 22
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 23
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 24
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 25
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 26
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Mitochondrial replacement techniques (MRTs) are designed to prevent the transmission of mitochondrial DNA (mtDNA) diseases from mother to child. While MRTs, if effective, could satisfy a desire of women seeking to have a genetically related child without the risk of passing on mtDNA disease, the technique raises significant ethical and social issues. It would create offspring who have genetic material from two women, something never sanctioned in humans, and would create mitochondrial changes that could be heritable (in female offspring), and therefore passed on in perpetuity. The manipulation would be performed on eggs or embryos, would affect every cell of the resulting individual, and once carried out this genetic manipulation is not reversible.

Mitochondrial Replacement Techniques considers the implications of manipulating mitochondrial content both in children born to women as a result of participating in these studies and in descendants of any female offspring. This study examines the ethical and social issues related to MRTs, outlines principles that would provide a framework and foundation for oversight of MRTs, and develops recommendations to inform the Food and Drug Administration’s consideration of investigational new drug applications.

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