npg
© 2015 Nature America, Inc. All rights reserved.
correspondence provide further information on appropriate dosing and would also provide invaluable information to patients, clinicians and public health officials on potential adverse events, safety risks and populations with greater or lesser clinical benefit. However, because these studies are often delayed or not conducted, legislators and the FDA may need to explore other policy mechanisms to ensure that mandatory post-approval trials are completed in a timely fashion9. For example, approval via the pilot program could be subject to a ‘sunset’ provision corresponding to the deadline for data submission from any post-approval studies. A second mechanism by which the US administration could encourage new countermeasures against lifethreatening bacterial infections is to institute prizes and boost federal funding for new diagnostics. Incentivizing innovation through prizes, which allow companies to ‘delink’ commercial reward from consumption volume10, is an increasingly popular approach. In 2014, for example, the UK announced the £10 (~$15.7) million Longitude Prize for the development of a point-of-care test that can identify when antibiotics are needed. In parallel, President Obama’s executive order called for a $25 million prize for “rapid, inexpensive and clinically relevant diagnostics.” Policymakers may consider expanding the pool of funds allocated to these prizes, particularly given their cost efficiency: for example, a rapid point-ofcare diagnostic for methicillin-resistant S. aureus is estimated to have a value to society exceeding $22 billion11. New models for funding basic and translational research could also foster antibiotic research12. Several strategic partnerships between government and industry have been launched, including the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) in the United States and the European Innovative Medicines initiative. In May 2013, BARDA announced a collaboration deal with GlaxoSmithKline (London) to develop a portfolio of antibacterial agents in which the agency would provide technical and financial support as well as share the development risks. These partnerships could be expanded to further reward academic researchers and developers of diagnostic devices that can be paired with existing antibiotics and products under development. 590
We believe that new antibacterial therapies with improved effectiveness are urgently needed to replenish clinicians’ armamentarium against evolving and increasingly drug-resistant pathogens that cause serious and life-threatening diseases. To stimulate antibiotic development, policymakers and regulators should focus on accelerating the development and approval of products with the highest potential improvement in patient outcomes. By focusing on targeted antibacterial therapies, accelerated pathways could advance precision medicine, in which treatment is tailored to each individual patient, and limit the risk of unsafe or ineffective drugs reaching the public. Note: Any Supplementary Information and Source Data files are available in the online version of the paper (doi:10.1038/nbt.3251). COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
Thomas J Hwang1,2, John H Powers3, Daniel Carpenter1,4 & Aaron S Kesselheim5 1Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. 2The Blackstone Group, London, UK. 3George
Washington University School of Medicine, Washington, DC, USA. 4Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts, USA. 5Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. e-mail: [email protected] or [email protected] 1. Federal Register. E.O. 13676. 79 FR 56931 (2014). 2. Applications for FDA Approval to Market a New Drug. 21 CFR §314.126 (2009). 3. Hwang, T.J., Carpenter, D. & Kesselheim, A.S. Science 344, 967–969 (2014). 4. Floyd, J.S. & Psaty, B.M. JAMA Intern. Med. 174, 1436–1437 (2014). 5. Outterson, K. et al. J. Law Med. Ethics 41, 688–696 (2013). 6. Kesselheim, A.S., Connolly, J., Rogers, J. & Avorn, J. Health Aff. (Millwood) 34, 438–446 (2015). 7. Silver, L.L. Nat. Biotechnol. 32, 1102–1104 (2014). 8. Falagas, M.E. Emerg. Infect. Dis. 20, 1170–1175 (2014). 9. Darrow, J.J., Avorn, J. & Kesselheim, A.S. N. Engl. J. Med. 371, 89–90 (2014). 10. Kesselheim, A.S. & Outterson, K. Yale J. Health Policy Law Ethics 11, 101–167 (2011). 11. Sertkaya, A. et al. Eastern Research Group Report for the US Department of Health and Human Services, report no. HHSP23337004T (ERG, Washington, DC, (2014). 12. Hwang, T.J., Carpenter, D. & Kesselheim, A.S. Sci. Transl. Med. 7, 276fs9 (2015).
The ethics of publishing human germline research To the Editor: A recent paper described the use of CRISPR-Cas9 to modify endogenous HBB, the gene that encodes b-globin, in single-celled, nonviable, triploid human zygotes—by-products of in vitro fertilization (IVF) created through fertilization of single eggs with two human sperm1. The research, published in the journal Protein & Cell, provoked a firestorm of controversy, reigniting old fears about gene therapy and raising new ethical concerns about human germline modification and ‘designer babies’. With clearly stated therapeutic goals, the scientists targeted endogenous HBB, the mutated form of which causes b-thalassemia. The research also probed questions about safety and efficacy. The Chinese research team reported three major findings, all of which had been previously reported in animal studies: (i) low overall editing efficiency, with only 4 of 28 embryos repaired using the guide template; (ii) genetic mosaicism, resulting from embryonic cell division before the corrections were
complete; and (iii) importantly, the detection of numerous off-target mutations1. Gene editing using the CRISPR-Cas9 system has been hailed as a major improvement on firstgeneration gene transfer technologies using viral vectors. Early gene transfer studies were inefficient, failed to persist in host cells, had short-lived transgene expression and suffered from off-target editing2. The HBB result suggests that dramatic improvements in gene targeting fidelity and specificity are needed before the CRISPR-Cas9 system can be used safely for therapies. In March, scientists and ethicists published essays in the journals Science and Nature putting forward recommendations for how human germline research should proceed3,4. Authors on both papers had commercial interests in germline editing technologies. The essays described the risks of human germline modification while promoting further research to better understand its safety and efficacy, including its off-target and unanticipated on-target effects. The authors of the Science essay discouraged
volume 33 NUMBER 6 JUNE 2015 nature biotechnology
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© 2015 Nature America, Inc. All rights reserved.
correspondence “[A]ny attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations”4. By contrast, the Nature commentary called for a stop to both clinical and basic human germline-focused research3. Follow-on recommendations reflect this dichotomy: the Society for Developmental Biology recommended a moratorium on clinical and basic research on human germline modification, whereas the International Society of Stem Cell Research (ISSCR) would suspend only clinical research on human embryo editing5,6. There is a gathering consensus to ban germline research that would make babies, but the dividing line has become whether in vitro research such as the Protein & Cell paper1 should be permitted. The CRISPR-Cas9 HBB study had been previously rejected at both Science and Nature, and it is unclear to what extent ethics reviews had a role in these decisions. Soon after the research was published, the quality of media reports ranged widely, with the main points of confusion being whether the researchers had edited a viable human embryo (they did not), whether the experiment was conducted unethically (it fully disclosed an ethics review) and whether designer babies were on the doorstep (not any time soon, if ever). In response to ethical and public concern, the editor of Protein & Cell defended the decision to publish the study as a matter of public service, saying, “[It] should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw…attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos”7. Concern about human germline modification is not new and has a forerunner in stem cell research. The ethical, legal and social implications of human induced pluripotent stem cells (hiPSCs) and germline modification were examined in a 2008 Hinxton Group consensus paper, and it was here that using new gene transfer technologies to create designer embryos was raised as an ethical ‘third rail’8. In particular, the report warned that “gamete research may facilitate applications directed towards ends that will be socially controversial, such as germline genetic modification for the correction of disease mutations, introduction of disease resistance, and other forms of biological enhancement”8. As in the CRISPR-
Cas9 case, there are central questions about the safety of germ cell induction from hiPSCs. If germ cells are made from pluripotent progenitors rather than obtained from IVF clinics, more research is required to solve problems of incomplete erasure of hiPSC epigenetic signatures, cellular maturity, the absence of pluripotent markers and the effects of exogenous reprogramming genes before these cells can be safely used for assisted reproductive therapies. The recent furor pertains to worries that germline modifications may be used to produce a living human. Without a clear understanding of the potential risks and benefits, such attempts would be tantamount to unethical human experimentation. We believe, however, that in vitro human germline research will help researchers to reach that understanding. The recommendations published in Science4 and by the ISSCR6 do not prohibit in vitro germline research, and we agree with this view. We offer one example of an appropriate and justified use of germline editing technology in human embryos. Engineered nucleases can be used to target specific loci in human embryos to address questions of early human development and fertility. This rationale relies on the fact that human development differs substantially from the development of other animals. For instance, activation of the embryonic genome occurs in the mouse at the two-cell stage at about 1 day after fertilization but occurs at the eightcell stage in human embryos at day 3. These and other differences (many still being unraveled) support the argument that assumptions about early development based on knockout experiments in other species might not hold true in human biology. In experiments like these, single-cell human zygotes would be edited, cultured to the blastocyst stage (2–4 days) and sequenced to measure editing efficiency, accuracy of targeting and the frequency of off-target effects. Once the first aim is achieved, the next series of experiments would directly target embryonic genes known to have crucial roles in development. By knocking out or interfering with the expression of these genes, one could measure their relative effects on development and blastocyst formation. Gene targeting could thus be used to track blastomeres and examine the progeny of a targeted cell and its contributions to the inner cell mass. This type of research would only be allowed on human embryos cultured before the fourteenth day or the beginning of the
nature biotechnology volume 33 NUMBER 6 JUNE 2015
primitive streak, an ethical guideline that is broadly accepted in more than a dozen countries. We see no serious ethical concerns with this approach, and with adequate stem cell research oversight (SCRO) and/or institutional review board (IRB) review, such research should be permitted. The research community should realize that publications detailing ethically permissible research on the human germline could prompt social concern and controversy. As any form of germline editing research could lead to gene therapy or other modifications of genetic traits, it is crucial that researchers and journals address the relevant ethical and social issues now. Authors submitting human germline research to journals should include a short section outlining steps that were taken for the approval of the study, including IRB and/ or SCRO review, and a clear explanation that embryos would be destroyed and not transferred for reproductive purposes. The scientific aims of such studies should emphasize the significance of the research. Investigators should not assume that other scientists understand details of the study, the social significance, or the potential medical and scientific benefits. These should be spelled out in detail. Investigators should also work closely with bioethicists to devise appropriate recommendations that can be placed in the discussion sections of submitted manuscripts. In addition, authors should not assume that the wider audience (which includes the general public, news organizations and policymakers) has thought carefully through the ethical issues of the research. They should fully disclose the ethical processes and guidelines that apply to their experiments. In tandem, journal editors should demand that authors address the main points of recommendations, guidelines and regulations cited here and elsewhere, such as the UK Human Fertilisation and Embryology Authority’s policy on embryo research9. This practice will go a long way to show that the experiment had editorial foresight and that the investigators thought through the potential social consequences of their research. Journals without external advisory boards with ethical expertise in this area should consider convening one. If the journal editors do not permit such a discussion, the authors should choose a journal that does. A researcher simply stating that the experiment had institutional ethics review is, in our view, insufficient. Similarly, a statement that the editors had 591
taken care and deliberation in considering the manuscript or that it was reviewed by the journal’s ethics advisors is also insufficient. One way of providing a full accounting of these deliberations is to publish a companion article to the original research that discusses the ethical, social and legal dimensions of controversial research. Although the use of nonviable embryos may assuage the moral fears of some, the main ethical dilemmas to emerge from the Protein & Cell study1 are its clinical aim, the attendant risks and the unregulated use of these technologies. It is in the interest of researchers and journals that publish socially contentious research to do so with full transparency and a justification and discussion of the ethical, legal and social issues. Now that the first human germline paper has been published, the scientific community and publishers should turn to consider the deeper justifications for research like this. At what point does the rush to publish a novel finding trump the ethical due diligence that must be given to such work? The results in the Protein & Cell study1 were anticipated in animal studies and, indeed, predicted by the Nature commentary3. Some CRISPR researchers believe that the experiment was predictable and provided little scientific insight. The gene-editing system was
outdated and susceptible to off-target problems10, raising questions of scientific merit and what journals, editors and referees should consider as they tread the line between science that is sensational and science that is truly groundbreaking. The dilemma of whether to publish the technical feat of human germline editing or work that moves the field forward in significant ways will continue to be an issue in this area. Given the controversial nature of human germline research and the moral weight of the materials used, what experiments investigating disease type, embryo stage, culture conditions and other incremental advances should go forward? Follow-on experiments become increasingly derivative, are worth exponentially less to science and are inversely related to the justification for using precious resources such as human embryos. At what point do such experiments become data-gathering exercises rather than answers to fundamental questions about human development and disease? More public discussion, with many different stakeholders, is required to settle these vexing but important questions. Arun Sharma & Christopher Thomas Scott Arun Sharma is at the Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Cardiovascular Institute, and
Christopher Thomas Scott is at the Center for Biomedical Ethics, Stanford University, Stanford, California, USA. e-mail: [email protected] ACKNOWLEDGMENTS C.T.S. is grateful for support from the Stanford Institute for Stem Cell Biology and Regenerative Medicine. C.T.S. was funded by a US National Institutes of Health CTSA grant (2U54TR000123). The authors thank Vittorio Sebastiano for his conceptual input. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Liang, P. et al. Protein Cell 6, 363–372 (2015). 2. Thomas, C.E., Ehrhardt, A. & Kay, M. Nat. Rev. Genet. 4, 346–358 (2003). 3. Lanphier, E., Urnov, F., Haecker, S.E., Werner, M. & Smolenski, J. Nature 519, 410–411 (2015). 4. Baltimore, B.D. et al. Science 348, 36–38 (2015). 5. Society for Developmental Biology. Position statement from the Society for Developmental Biology on genomic editing in human embryos. http://www.sdbonline.org/ uploads/files/SDBgenomeeditposstmt.pdf (24 April 2015). 6. International Society of Stem Cell Research. The ISSCR statement on human germline genome modification. http://www.isscr.org/home/about-us/ news-press-releases/2015/2015/03/19/statementon-human-germline-genome-modification (19 March 2015). 7. Zhang, X. Protein Cell 6, 313 (2015). 8. The Hinxton Group. Science, ethics and policy challenges of pluripotent stem cell-derived gametes. http:// www.hinxtongroup.org/consensus_hg08_final.pdf (11 April 2008). 9. Human Fertilisation and Embryology Authority. Human Embryo Research. http://www.hfea.gov.uk/161.html (9 July 2012). 10. Kaiser, J. & Normile, D. Science 348, 486–487 (2015).
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© 2015 Nature America, Inc. All rights reserved.
correspondence
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volume 33 NUMBER 6 JUNE 2015 nature biotechnology
CORRIGENDA
Corrigendum: The ethics of publishing human germline research Arun Sharma & Christopher Thomas Scott Nat. Biotechnol. 33, 590–592 (2015); published online 9 June 2015; corrected after print 9 June 2015
npg
© 2015 Nature America, Inc. All rights reserved.
In the version of this article initially published, a name in the acknowledgments was spelled as Vittoria, rather than Vittorio, Sebastiano. The error has been corrected in the HTML and PDF versions of the article.
nature biotechnology
© 2015 Nature America, Inc. All rights reserved.
correspondence provide further information on appropriate dosing and would also provide invaluable information to patients, clinicians and public health officials on potential adverse events, safety risks and populations with greater or lesser clinical benefit. However, because these studies are often delayed or not conducted, legislators and the FDA may need to explore other policy mechanisms to ensure that mandatory post-approval trials are completed in a timely fashion9. For example, approval via the pilot program could be subject to a ‘sunset’ provision corresponding to the deadline for data submission from any post-approval studies. A second mechanism by which the US administration could encourage new countermeasures against lifethreatening bacterial infections is to institute prizes and boost federal funding for new diagnostics. Incentivizing innovation through prizes, which allow companies to ‘delink’ commercial reward from consumption volume10, is an increasingly popular approach. In 2014, for example, the UK announced the £10 (~$15.7) million Longitude Prize for the development of a point-of-care test that can identify when antibiotics are needed. In parallel, President Obama’s executive order called for a $25 million prize for “rapid, inexpensive and clinically relevant diagnostics.” Policymakers may consider expanding the pool of funds allocated to these prizes, particularly given their cost efficiency: for example, a rapid point-ofcare diagnostic for methicillin-resistant S. aureus is estimated to have a value to society exceeding $22 billion11. New models for funding basic and translational research could also foster antibiotic research12. Several strategic partnerships between government and industry have been launched, including the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) in the United States and the European Innovative Medicines initiative. In May 2013, BARDA announced a collaboration deal with GlaxoSmithKline (London) to develop a portfolio of antibacterial agents in which the agency would provide technical and financial support as well as share the development risks. These partnerships could be expanded to further reward academic researchers and developers of diagnostic devices that can be paired with existing antibiotics and products under development. 590
We believe that new antibacterial therapies with improved effectiveness are urgently needed to replenish clinicians’ armamentarium against evolving and increasingly drug-resistant pathogens that cause serious and life-threatening diseases. To stimulate antibiotic development, policymakers and regulators should focus on accelerating the development and approval of products with the highest potential improvement in patient outcomes. By focusing on targeted antibacterial therapies, accelerated pathways could advance precision medicine, in which treatment is tailored to each individual patient, and limit the risk of unsafe or ineffective drugs reaching the public. Note: Any Supplementary Information and Source Data files are available in the online version of the paper (doi:10.1038/nbt.3251). COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
Thomas J Hwang1,2, John H Powers3, Daniel Carpenter1,4 & Aaron S Kesselheim5 1Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. 2The Blackstone Group, London, UK. 3George
Washington University School of Medicine, Washington, DC, USA. 4Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts, USA. 5Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. e-mail: [email protected] or [email protected] 1. Federal Register. E.O. 13676. 79 FR 56931 (2014). 2. Applications for FDA Approval to Market a New Drug. 21 CFR §314.126 (2009). 3. Hwang, T.J., Carpenter, D. & Kesselheim, A.S. Science 344, 967–969 (2014). 4. Floyd, J.S. & Psaty, B.M. JAMA Intern. Med. 174, 1436–1437 (2014). 5. Outterson, K. et al. J. Law Med. Ethics 41, 688–696 (2013). 6. Kesselheim, A.S., Connolly, J., Rogers, J. & Avorn, J. Health Aff. (Millwood) 34, 438–446 (2015). 7. Silver, L.L. Nat. Biotechnol. 32, 1102–1104 (2014). 8. Falagas, M.E. Emerg. Infect. Dis. 20, 1170–1175 (2014). 9. Darrow, J.J., Avorn, J. & Kesselheim, A.S. N. Engl. J. Med. 371, 89–90 (2014). 10. Kesselheim, A.S. & Outterson, K. Yale J. Health Policy Law Ethics 11, 101–167 (2011). 11. Sertkaya, A. et al. Eastern Research Group Report for the US Department of Health and Human Services, report no. HHSP23337004T (ERG, Washington, DC, (2014). 12. Hwang, T.J., Carpenter, D. & Kesselheim, A.S. Sci. Transl. Med. 7, 276fs9 (2015).
The ethics of publishing human germline research To the Editor: A recent paper described the use of CRISPR-Cas9 to modify endogenous HBB, the gene that encodes b-globin, in single-celled, nonviable, triploid human zygotes—by-products of in vitro fertilization (IVF) created through fertilization of single eggs with two human sperm1. The research, published in the journal Protein & Cell, provoked a firestorm of controversy, reigniting old fears about gene therapy and raising new ethical concerns about human germline modification and ‘designer babies’. With clearly stated therapeutic goals, the scientists targeted endogenous HBB, the mutated form of which causes b-thalassemia. The research also probed questions about safety and efficacy. The Chinese research team reported three major findings, all of which had been previously reported in animal studies: (i) low overall editing efficiency, with only 4 of 28 embryos repaired using the guide template; (ii) genetic mosaicism, resulting from embryonic cell division before the corrections were
complete; and (iii) importantly, the detection of numerous off-target mutations1. Gene editing using the CRISPR-Cas9 system has been hailed as a major improvement on firstgeneration gene transfer technologies using viral vectors. Early gene transfer studies were inefficient, failed to persist in host cells, had short-lived transgene expression and suffered from off-target editing2. The HBB result suggests that dramatic improvements in gene targeting fidelity and specificity are needed before the CRISPR-Cas9 system can be used safely for therapies. In March, scientists and ethicists published essays in the journals Science and Nature putting forward recommendations for how human germline research should proceed3,4. Authors on both papers had commercial interests in germline editing technologies. The essays described the risks of human germline modification while promoting further research to better understand its safety and efficacy, including its off-target and unanticipated on-target effects. The authors of the Science essay discouraged
volume 33 NUMBER 6 JUNE 2015 nature biotechnology
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© 2015 Nature America, Inc. All rights reserved.
correspondence “[A]ny attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations”4. By contrast, the Nature commentary called for a stop to both clinical and basic human germline-focused research3. Follow-on recommendations reflect this dichotomy: the Society for Developmental Biology recommended a moratorium on clinical and basic research on human germline modification, whereas the International Society of Stem Cell Research (ISSCR) would suspend only clinical research on human embryo editing5,6. There is a gathering consensus to ban germline research that would make babies, but the dividing line has become whether in vitro research such as the Protein & Cell paper1 should be permitted. The CRISPR-Cas9 HBB study had been previously rejected at both Science and Nature, and it is unclear to what extent ethics reviews had a role in these decisions. Soon after the research was published, the quality of media reports ranged widely, with the main points of confusion being whether the researchers had edited a viable human embryo (they did not), whether the experiment was conducted unethically (it fully disclosed an ethics review) and whether designer babies were on the doorstep (not any time soon, if ever). In response to ethical and public concern, the editor of Protein & Cell defended the decision to publish the study as a matter of public service, saying, “[It] should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw…attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos”7. Concern about human germline modification is not new and has a forerunner in stem cell research. The ethical, legal and social implications of human induced pluripotent stem cells (hiPSCs) and germline modification were examined in a 2008 Hinxton Group consensus paper, and it was here that using new gene transfer technologies to create designer embryos was raised as an ethical ‘third rail’8. In particular, the report warned that “gamete research may facilitate applications directed towards ends that will be socially controversial, such as germline genetic modification for the correction of disease mutations, introduction of disease resistance, and other forms of biological enhancement”8. As in the CRISPR-
Cas9 case, there are central questions about the safety of germ cell induction from hiPSCs. If germ cells are made from pluripotent progenitors rather than obtained from IVF clinics, more research is required to solve problems of incomplete erasure of hiPSC epigenetic signatures, cellular maturity, the absence of pluripotent markers and the effects of exogenous reprogramming genes before these cells can be safely used for assisted reproductive therapies. The recent furor pertains to worries that germline modifications may be used to produce a living human. Without a clear understanding of the potential risks and benefits, such attempts would be tantamount to unethical human experimentation. We believe, however, that in vitro human germline research will help researchers to reach that understanding. The recommendations published in Science4 and by the ISSCR6 do not prohibit in vitro germline research, and we agree with this view. We offer one example of an appropriate and justified use of germline editing technology in human embryos. Engineered nucleases can be used to target specific loci in human embryos to address questions of early human development and fertility. This rationale relies on the fact that human development differs substantially from the development of other animals. For instance, activation of the embryonic genome occurs in the mouse at the two-cell stage at about 1 day after fertilization but occurs at the eightcell stage in human embryos at day 3. These and other differences (many still being unraveled) support the argument that assumptions about early development based on knockout experiments in other species might not hold true in human biology. In experiments like these, single-cell human zygotes would be edited, cultured to the blastocyst stage (2–4 days) and sequenced to measure editing efficiency, accuracy of targeting and the frequency of off-target effects. Once the first aim is achieved, the next series of experiments would directly target embryonic genes known to have crucial roles in development. By knocking out or interfering with the expression of these genes, one could measure their relative effects on development and blastocyst formation. Gene targeting could thus be used to track blastomeres and examine the progeny of a targeted cell and its contributions to the inner cell mass. This type of research would only be allowed on human embryos cultured before the fourteenth day or the beginning of the
nature biotechnology volume 33 NUMBER 6 JUNE 2015
primitive streak, an ethical guideline that is broadly accepted in more than a dozen countries. We see no serious ethical concerns with this approach, and with adequate stem cell research oversight (SCRO) and/or institutional review board (IRB) review, such research should be permitted. The research community should realize that publications detailing ethically permissible research on the human germline could prompt social concern and controversy. As any form of germline editing research could lead to gene therapy or other modifications of genetic traits, it is crucial that researchers and journals address the relevant ethical and social issues now. Authors submitting human germline research to journals should include a short section outlining steps that were taken for the approval of the study, including IRB and/ or SCRO review, and a clear explanation that embryos would be destroyed and not transferred for reproductive purposes. The scientific aims of such studies should emphasize the significance of the research. Investigators should not assume that other scientists understand details of the study, the social significance, or the potential medical and scientific benefits. These should be spelled out in detail. Investigators should also work closely with bioethicists to devise appropriate recommendations that can be placed in the discussion sections of submitted manuscripts. In addition, authors should not assume that the wider audience (which includes the general public, news organizations and policymakers) has thought carefully through the ethical issues of the research. They should fully disclose the ethical processes and guidelines that apply to their experiments. In tandem, journal editors should demand that authors address the main points of recommendations, guidelines and regulations cited here and elsewhere, such as the UK Human Fertilisation and Embryology Authority’s policy on embryo research9. This practice will go a long way to show that the experiment had editorial foresight and that the investigators thought through the potential social consequences of their research. Journals without external advisory boards with ethical expertise in this area should consider convening one. If the journal editors do not permit such a discussion, the authors should choose a journal that does. A researcher simply stating that the experiment had institutional ethics review is, in our view, insufficient. Similarly, a statement that the editors had 591
taken care and deliberation in considering the manuscript or that it was reviewed by the journal’s ethics advisors is also insufficient. One way of providing a full accounting of these deliberations is to publish a companion article to the original research that discusses the ethical, social and legal dimensions of controversial research. Although the use of nonviable embryos may assuage the moral fears of some, the main ethical dilemmas to emerge from the Protein & Cell study1 are its clinical aim, the attendant risks and the unregulated use of these technologies. It is in the interest of researchers and journals that publish socially contentious research to do so with full transparency and a justification and discussion of the ethical, legal and social issues. Now that the first human germline paper has been published, the scientific community and publishers should turn to consider the deeper justifications for research like this. At what point does the rush to publish a novel finding trump the ethical due diligence that must be given to such work? The results in the Protein & Cell study1 were anticipated in animal studies and, indeed, predicted by the Nature commentary3. Some CRISPR researchers believe that the experiment was predictable and provided little scientific insight. The gene-editing system was
outdated and susceptible to off-target problems10, raising questions of scientific merit and what journals, editors and referees should consider as they tread the line between science that is sensational and science that is truly groundbreaking. The dilemma of whether to publish the technical feat of human germline editing or work that moves the field forward in significant ways will continue to be an issue in this area. Given the controversial nature of human germline research and the moral weight of the materials used, what experiments investigating disease type, embryo stage, culture conditions and other incremental advances should go forward? Follow-on experiments become increasingly derivative, are worth exponentially less to science and are inversely related to the justification for using precious resources such as human embryos. At what point do such experiments become data-gathering exercises rather than answers to fundamental questions about human development and disease? More public discussion, with many different stakeholders, is required to settle these vexing but important questions. Arun Sharma & Christopher Thomas Scott Arun Sharma is at the Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Cardiovascular Institute, and
Christopher Thomas Scott is at the Center for Biomedical Ethics, Stanford University, Stanford, California, USA. e-mail: [email protected] ACKNOWLEDGMENTS C.T.S. is grateful for support from the Stanford Institute for Stem Cell Biology and Regenerative Medicine. C.T.S. was funded by a US National Institutes of Health CTSA grant (2U54TR000123). The authors thank Vittorio Sebastiano for his conceptual input. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Liang, P. et al. Protein Cell 6, 363–372 (2015). 2. Thomas, C.E., Ehrhardt, A. & Kay, M. Nat. Rev. Genet. 4, 346–358 (2003). 3. Lanphier, E., Urnov, F., Haecker, S.E., Werner, M. & Smolenski, J. Nature 519, 410–411 (2015). 4. Baltimore, B.D. et al. Science 348, 36–38 (2015). 5. Society for Developmental Biology. Position statement from the Society for Developmental Biology on genomic editing in human embryos. http://www.sdbonline.org/ uploads/files/SDBgenomeeditposstmt.pdf (24 April 2015). 6. International Society of Stem Cell Research. The ISSCR statement on human germline genome modification. http://www.isscr.org/home/about-us/ news-press-releases/2015/2015/03/19/statementon-human-germline-genome-modification (19 March 2015). 7. Zhang, X. Protein Cell 6, 313 (2015). 8. The Hinxton Group. Science, ethics and policy challenges of pluripotent stem cell-derived gametes. http:// www.hinxtongroup.org/consensus_hg08_final.pdf (11 April 2008). 9. Human Fertilisation and Embryology Authority. Human Embryo Research. http://www.hfea.gov.uk/161.html (9 July 2012). 10. Kaiser, J. & Normile, D. Science 348, 486–487 (2015).
npg
© 2015 Nature America, Inc. All rights reserved.
correspondence
592
volume 33 NUMBER 6 JUNE 2015 nature biotechnology
CORRIGENDA
Corrigendum: The ethics of publishing human germline research Arun Sharma & Christopher Thomas Scott Nat. Biotechnol. 33, 590–592 (2015); published online 9 June 2015; corrected after print 9 June 2015
npg
© 2015 Nature America, Inc. All rights reserved.
In the version of this article initially published, a name in the acknowledgments was spelled as Vittoria, rather than Vittorio, Sebastiano. The error has been corrected in the HTML and PDF versions of the article.
nature biotechnology
