Developing World Bioethics ISSN 1471-8731 (print); 1471-8847 (online)

doi:10.1111/dewb.12108

NO ETHICAL DIVIDE BETWEEN CHINA AND THE WEST IN HUMAN EMBRYO RESEARCH XIAOMEI ZHAI, VINCENT NG AND REIDAR LIE

Keywords China, research ethics, genetics

Abstract This is a discussion of the reaction to the recent research article publication in the journal Protein & Cell by a group of scientists at Sun Yat-sen University using the CRISPR/Cas9 technique on editing non-viable human zygotes. Many commentators condemned the Chinese scientists for overstepping ethical boundaries long accepted in Western countries and accused China of having lax regulations on genomic research in general. We argue that not only did this research follow strict ethical standards and fully comply with current regulations, but China also has a well-developed regulatory framework governing such research comparable to many developed countries. We see the reactions among Western commentators as a misunderstanding of the current situation and an expression of a lack of willingness to acknowledge China as an equal partner in the international debate about proper limits to the development of new biotechnologies.

INTRODUCTION On March 19, 2015 a group of prominent scientists published a Perspectives article in Science, calling for a “prudent path forward for genomic engineering and germline gene modification”.1 Their worries were raised by the CRISPR/Cas9 technology, which can be used to edit precisely genomes of almost any organisms. The technique has been extensively applied to edit many mammalian genomes including mice, monkey and human stem cells.2 The group of scientists expressed strong concern on using this technology to edit human germline cells that can potentially turn into viable human embryos. One of their main recommendations was that steps should be taken to “strongly discourage even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implica1 D. Baltimore, D. et al. A prudent path forward for genomic engineering and germline gene modification. Science 215; 348: 36–38. 2 O. Mali et al. Cas 9 as a versatile tool for engineering biology. Nature Methods 213; 10: 957–63.

tions of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated).” It was not mentioned in this article that there were rumors that such experiments had already taken place in China, and that the two journals Science and Nature had already refused publication of this research out of ethical concerns. “Countries with lax jurisdictions” could easily be read as a reference to China. On April 1, 2015, such research using the CRISPR/Cas9 technique on editing non-viable human zygotes was indeed published by Dr. Huang’s research team at Sun Yat-sen University in Guangzhou, China in the journal Protein & Cell.3 It immediately raised a firestorm of international criticism. In the US, National Public Radio’s (NPR) headline was “critics lash out at Chinese scientists who edited DNA in human embryos”. The research was condemned by many scientists and watchdog groups, who argue the research is unsafe, premature and raises disturbing ethical 3 P. Liang et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell May 2015; 6: 363–372.

Address for correspondence: Reidar K. Lie, University of Bergen, Department of Philosophy, Sydnesplassen 12, 5020 Bergen NORWAY. Email: [email protected] Conflict of interest statement: No conflicts declared. © 2016 John Wiley & Sons Ltd

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concerns. Dr. Marcy Darnovsky of the Center for Genetics and Society condemned the research by saying “No researcher should have the moral warrant to flout the globally widespread policy agreement against modifying the human germline”.4 Many of the news items referred to specific worries about China and the supposed lax oversight on genomic research. Most explicitly, the New York Times published an article on June 29, 2015 titled “A Scientific Ethical Divide Between China and the West”5, quoting a bioethicist from Hong Kong who portrayed Chinese genetics researchers as being willing to try anything first and ask questions later, carrying out research in the scientific community in the West unanimously agree as premature. The article in the Times portrayed a sharp ethical divide between China and the West, reporting worries that “medical researchers in China are stepping over ethical boundaries long accepted in the West”.

LACK OF CONSENSUS ABOUT THE ETHICS OF GERMLINE MODIFICATION First, there is actually no consensus among biomedical scientists, policy makers or the general public that the research done by Dr. Huang’s research team was ethically unacceptable. In fact, this line of research would be legal in many US states and European countries even though the NIH cannot fund such research because of the 1996 US law known as Dickey-Wicker amendment that specifically bans federal funding on works that involves creation or destruction of human embryos.6 A lot of Western media focused on sensational headlines like “Chinese shocks the world by genetically engineering human embryo”,7 “Mad scientists in China attempt to create genetically modified babies”8,

accusing the Chinese of trying to make “designer babies”9, and calling China a “Wild West” of genetic research10. Many did not carefully explain what Huang and his team actually did and some did not even mention they used nonviable zygotes.11 On closer look, Huang’s research team actually took very careful ethical precautions in conducting their research. First of all, they used dispermic tripronuclear (3PN) zygotes, eggs that have been abnormally fertilized by 2 sperms and therefore contains 3 sets of chromosomes vs the normal 2 sets of chromosomes in an actual viable embryo. These 3PN zygotes are quite common and constitute about 3-5% of all the fertilized eggs generated in an IVF setting due to the reduced ability of the egg to trigger exclusion to polyspermy.12 These doubly-fertilized eggs would generally undergo the first stage of development, reach a stage that looks like a ball of cells (blastocysts) and no further. They would never develop any organs, sensory cells, neurons, blood cells, or any noticeable differentiation that would remotely resemble anything like a fetus.13 Moreover, the research team only allowed these zygotes to develop for about 48 hours to reach the 8-cells stage before they are destroyed and analyzed for efficacy of the target gene editing. In comparison, scientists who create embryonic stem cells from embryos allow the embryos to grow for about 5-6 days and wait for the embryo to reach the 100 to 300-cells stage before the developing embryos are destroyed for harvesting of embryonic stem cells. Dr. Huang’s research clearly complies with generally accepted international guidelines on research on human embryos by destroying these zygotes very shortly after modification (14 days being the current US guidelines).14 Furthermore, they discussed in their research paper that the relatively low efficiency of successful genome editing and the high incidents of off-target replacement is an obstacle of using this technique on viable human embryos. They also clearly indicated that unless a

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S. Reardon. Ethics of Embryo editing paper divides scientists. Nature News doi:10.1038/nature2015.17410. Gina Kolata. Chinese Scientists Edit Genes of Human Embryos, Raising Concerns. New York Times April 24, 2015. Available at: http://www.nytimes.com/2015/04/24/health/chinesescientists-edit-genes-of-human-embryos-raising-concerns.html [Accessed 8 Dec 2015]. 5 Didi Karen Tatlow. A Scientific Ethical Divide between China and the West. New York Times June 29, 2015. Available at http://www.nytimes. com/2015/06/30/science/a-scientific-ethical-divide-between-china-and-west. html [Accessed 8 Dec 2015]. 6 M. Kearl. Dickey-Wicker Amendment, 1996. Embryo Project Encyclopedia (2010-08-27). ISSN: 1940-5030. Available at: https://embryo.asu.edu/ pages/dickey-wicker-amendment-1996#sthash.ifeYO2fd.dpuf [Accessed 8 Dec 2015]. 7 China shocks the world by genetically engineering human embryos. Telegraph 23 April 2015. Available at: http://www.telegraph.co.uk/news/ science/11558305/China-shocks-world-by-genetically-engineering-humanembryos.html [Accessed 8 Dec 2015]. 8 Mad Scientists in China attempt to create genetically modified babies didn’t go well. April 24, 2015. Available at: http://www.lifenews.com/ 2015/04/24/mad-scientists-in-china-attempt-to-create-genetically-modifiedbabies-it-didnt-go-well/ [Accessed 8 Dec 2015].

9 Designer baby controversy: scientists edit genome of human embryo. CBS News April 24, 2015. Available at: http://www.cbsnews.com/ news/designer-baby-controversy-scientists-edit-genome-of-human-embryo/ [Accessed 8 Dec 2015]. 10 Op. cit., footnote 7. 11 Researchers ‘edit’ human embryo genes for the first time ever. Available at: http://www.wired.co.uk/news/archive/2015-04/23/gene-editinghuman-embryos-first-controversial-study; [Accessed 8 Dec 2015]. Chinese edit human embryo – the first step in rewriting mankind. Available at: https://therearenosunglasses.wordpress.com/2015/05/02/chinese-edit-humanembryo-the-first-step-in-rewriting-mankind/ [Accessed 8 Dec 2015]. 12 H. Feng & Herslag A. Fertilization Abnormalities Following Human In Vitro Fertilization and Intracytoplasmic Sperm Injection. Microscopy Resch & Technique 2003; 61:358–361. 13 HJ Kang & Rosenwaks Z. Triploidy – the breakdown of monogamy between sperm and egg. Int J. Dev. Biol 2008; 52:449–454. 14 American Congress of Obstetricians and Gynecologists Committee Opinion Number 347 Nov 2006. Available at: http://m.acog.org/ResourcesAnd-Publications/Committee-Opinions/Committee-on-Ethics/Using-Preim plantation-Embryos-for-Research?IsMobileSet=true [Accessed 8 Dec 2015].

© 2016 John Wiley & Sons Ltd

No Ethical Divide between China and the West method of higher fidelity is found, this technique should not be applied to clinical research on actual human embryos. In essence, they used a model system (cells that have similar properties to embryos but are not real viable embryos) that is arguably better than other animal model systems to determine how effective this CRISPR/Cas9 technique is in editing genome in human cells and concluded that the technique should not be applied to real viable embryos. Many prominent scientists and bioethicists in China and abroad agree that there is “nothing wrong with this kind of research”.

THE CHINESE REGULATORY FRAMEWORK Contrary to what is claimed by many critics, there is an extensive regulatory framework in place in China. We have elsewhere provided an overview of relevant Chinese regulations.15 Briefly, these include The Interim Procedures for Human Genetic Resources Management by the National Health and Family Planning Commission (former Ministry of Health or MoH) in 1998, Ethical Principles on Artificial Reproductive Technology (ART) by MoH in 2001 and Ethical Principles for ART and the Human Sperm Bank by MoH in 2003, and the Good Clinical Practice by the Chinese FDA from 2003.16 In 2007 the Ministry of Health introduced regulations regarding The Ethical Review of Biomedical Research Involving Human Subjects. These mandate IRB review and follow international standards for such review. All of these regulations are already in compliance with universally accepted international documents including the Nuremburg Code, Helsinki Declaration and CIOMS/WHO International Ethical Guidelines on Biomedical Research involving Human Subjects. In 2012 the initial draft of The Regulation of the Human Genetic Resources was published by the State Council for public comments. Although the regulation has not officially come into force yet, it would replace the former interim measures of 1998. The regulation officially requires IRB review for all genetic research and places further specific emphasis on genetic research. The draft requires that the collection and storage of human genetic samples should abide by principles of autonomy and informed consent. Before sample collection, written informed consent shall be offered to the donor to explain the purpose, usage, potential health risks, interest-sharing plans, privacy protection and other necessary relevant information about the research. Subjects have the right to quit unconditionally at

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any time. It also requires that re-consent should be requested if samples are used for other purposes beyond the initial consent. Between 1991 and 1999 Chinese Food and Drug Administration (CFDA) and Ministry of Health (MOH) promulgated a number of regulations on somatic gene modifications which stress on securing safety and implementing informed consent requirement. So far only clinical trials of somatic gene modification are legally permissible in China. In the Article 3.7 and 3.9 of the Technical Norms on Human Assisted Reproduction (2003) promulgated by MOH it is clearly stipulated that “gene manipulation on human gamete, zygote and embryo for the purpose of reproduction is banned”. It should therefore be clear that the Chinese regulatory framework is not substantially different from that found in other countries. There are informed consent requirements, requirements of IRB review that includes assessments of the risks and benefits of the research, specific regulations regarding genetic research and, most importantly, and regulations regarding gene manipulation of zygotes and embryos. Again, similar to what is the case in many Western countries, such research is not strictly prohibited, but is definitely banned “for the purpose of reproduction”. Specifically, the use of non-viable 3PN zygotes would definitely not be forbidden since these zygotes could not be used for the purpose of reproduction. As long as the research is done on cells that will never develop into a human fetus, there are no worries about uncertain risks to future fetuses or babies. We argue that this research has actually provided valuable insights on the shortcomings of the Crispr-Cas9 technique and highlighted that more data are needed to evaluate the risks, before the technique could be applied for any potential therapeutic purpose. In fact, the Chinese regulations are already in line with the March 19 Science article. It urges restraint on “germline genome modification for clinical application in humans”. At least according to one of the authors of this article, Hank Greely, this does not rule out research on ex vivo human embryos that will never develop into a human fetus.17 Apparently, it is only when you regard these doubly-fertilized non-viable eggs regularly discarded by fertility clinics as actual “embryos” or fully human would ethical concerns arise, and clearly many people do not share that view, neither in China nor in other countries.

THE POLICY DISCUSSIONS IN CHINA Some critics believe some sort of red line has been crossed. Even though the research published use 3PN

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Z. Wang et al. Following the giant’s paces-governance issues and bioethical reflections in China. BMC Medical Ethics 2014; 15:79–87. 16 Original Chinese regulations: 2001年9月中国卫生部科教司(科研教育 司)签发了关于《实施人类辅助生殖技术的伦理原则》的规范性文件 (卫科教发157号文件),2003年10月1日中国卫生部颁布实施了《人类辅 助生殖技术和人类精子库伦理原则》

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H. Greely. Of science, CRISPR-CAS9, and Asilomar. Law and Biosciences Blog 2015. Available at: http://blogs.law.stanford.edu/lawand biosciences/2015/04/04/of-science-crispr-cas9-and-asilomar/ [Accessed 8 Dec 2015].

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zygotes this time, it will just be a matter of time before some other scientists in China or elsewhere will attempt to modify actual embryos and even attempt to develop them until birth. The regulations in China may be similar to those found elsewhere, but the critics apparently believe that many people do not adhere to the regulations and enforcement is lacking in China. This cannot be a more mistaken view in our opinion. As stated before, currently Chinese regulations already ban genomic research for reproduction purposes. Both before and after the publication of the experiments, there has been an intense public debate about the ethical issues raised by such research. Multiple Chinese newspapers have extensively reported on this research paper, and positions similar to those in other countries have been extensively debated. For instance, renowned Chinese bioethics Prof Qiu Renzong, after he was made aware of the experimental details, had no serious ethical objections to their research. On responding to a request from Chinese Science News (中国科 学报), he pointed out that this line of research involving these abnormal, non-viable fertilized eggs is ethically defensible. He further stated that there is currently no clinical research involving genomic editing of actual human embryos going on in China. Simply conducting scientific research on non-viable ex vivo embryos has not crossed any red lines on the fundamental worldwide ethical consensus of not editing human germline cells. He further suggested that if this technique can be developed to the point that it is safe and efficacious, it could be beneficial to mankind. He also pointed out that there are still debates about research on human and embryonic stem cells in the society and scientists who conduct such research should conduct more thorough discussions with experts in ethics, law, social sciences and the general public about these research. As for conducting research on genomic editing on actual embryos, Prof Qiu agrees that there should be a moratorium at present until more discussion on what ethical questions it will engender, what could or could not be done, and under what circumstances may research of this kind enter clinical trial, etc. have been thoroughly and comprehensively discussed.18 More critical points of view are also presented. Prof Zhang Xin-Qing of the School of Social Sciences and Humanities at PUMC stated that there are scientists in China who would for the sake of trying to “get there before anyone else” in their research field, would sometimes disregard ethical discussion and go ahead with their research project first. This is manifested by the current state of various attempts on clinical applications of somatic stem cell research in China, which Prof Zhang described as “being a chaotic scene”. He pointed out that more considerations and legislation is needed in China. In the absence of a comprehensive guidelines and governance, he 18

http://news.sciencenet.cn/htmlnews/2015/6/320276.shtm [In Chinese] [Accessed 8 Dec 2015].

suggests that this kind of research be suspended. Prof. Zhang also criticized the journal Protein & Cell for publishing the article two days after receiving it. The unusually fast turnaround time may render people to think that their review process had not been too careful.19 Vice Director Ren Lu-feng of Beijing Institute of Genomics, Chinese Academy of Sciences, pointed out that the high profile international discussion about this research has sent some warning signals to scientists in China. He frankly cautioned scientists in China saying “scientific research is not without any boundaries” and expressed concerns that many Chinese scientists do not take ethical considerations seriously. He said that there should be stronger governance and greater accountability on research activities in general. He suggested that IRB review board should conduct more follow up investigations. The University/Institution department, the MOH, funder and auditors of research funding all have responsibility to make sure that scientific research projects strictly comply with ethical standards.20 All these show that there are vigorous ethical discussions going on about governance of scientific research involving human embryos in China, similar to what we see in other countries. There seems to be a consensus that stronger governance, stricter enforcement of existing legislation, and greater accountability is needed in China governing research involving human embryos. However, we cannot disagree more strongly to some outsiders’ assessment that China is a place with lax legislations or no regulatory oversight on human embryo research and scientists there show no respects for ethical considerations. Rather than portraying a sharp ethical divide between China and the West, we should recognize that there is an ongoing international debate on appropriate ethical boundaries for the development of these new technologies, where individual countries develop national policy frameworks with active involvement of and learning from the experience and expertise available in other countries.

WHY THE CRITICISM OF CHINA? In light of the absence of consensus that this research was morally wrong, the presence of regulations in China that are comparable to those in other countries, and evidence of debate in the Chinese media about this research, why, then, the almost universal condemnation of this research in reputable Western media?21 We believe there seems to be a prevalent attitude in the west that “if the Chinese do it, 19

ibid http://www.thepaper.cn/newsDetail_forward_1329087 [In Chinese] [Accessed 8 Dec 2015]. 21 Article by Gina Kolata in New York Times, op cit. footnote 4. Chinese manipulation of human embryo genes draws rebuke. Wall Street Journal April 23, 2015. Available at: http://www.wsj.com/articles/newadvance-in-gene-editing-reported-1429804820 [Accessed 8 Dec 2015]. 20

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No Ethical Divide between China and the West there must be something wrong with it”. Newspapers, journalists, and science writers all find it easy to publish materials that are critical of China. It seems much more difficult to report on positive developments, or paint a more nuanced picture of what is actually going on in China. The New York Times, for example, chose not to publish a letter from one of us, trying to correct what we see as misrepresentations in the report by Didi Karen Tatlow. We believe that there is also another reason for the disproportionate criticism of the Chinese research, related to reasons that may have motivated the publication of the Perspectives article. We do not at all question that the authors of this piece are genuinely motivated by a desire to promote responsible research according to the highest ethical standards. It is reasonable to assume that there are also more immediate concerns that have motivated publication at exactly this time. This is similar to previous calls for self-regulations. The historian of science Nathaniel Comfort claimed in a recent Nation review that one of the motivations for the call for a self-imposed moratorium in 1974 on recombinant DNA research was that scientists feared “a massive clampdown from on high”.22 Cambridge, MA, had already banned such research then. Similar concerns are raised today. A group of scientists associated with a company that relies on genome-editing techniques said the following in a commentary in Nature: “It is thought that studies involving the use of genomeediting tools to modify the DNA of human embryos will be published shortly. There are grave concerns regarding the ethical and safety implications of this research. There is also fear of the negative impact it could have on important work involving the use of genome-editing techniques in somatic (non-reproductive) cells.”23 We do not at all deny the importance of such fears and the legitimacy of these concerns as a motivation to advocate self-regulation of science. The prohibition to fund embryonic stem cell research by the US federal government under the Bush administration probably has delayed important and potentially useful research. New restrictions now could easily have the same effect. Now, there seems to be fear that indiscriminate and unregulated use of the Crispr/Cas9 genome editing technology may lead to a similar prohibition of its use, which will undoubtedly seriously set back research progress in the USA. This might have prompted some scientists to call for more stringent self-regulation and a world-wide moratorium on its use of human germline cells. However, painting China as a country with “lax regulations” and little governance on this kind of research is clearly misguided and would not add any credence to this notion. On Sep 18, 2018. The British 22

N. Comfort. Can we cure genetic diseases without slipping into eugenics. Nation July 16, 2015. 23 E. Lanphier et al. Don’t Edit the Human Germline. Nature 2015: 519; 410–411.

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newspaper Guardian reported that stem cell Scientist Kathy Niakan from the Francis Crick Institute in London asked the UK government for a license to perform genome editing on human embryos using the Crispr/Cas9 technique.24 This clearly shows scientists from outside of China are showing increased interests to perform genome editing experiments on human embryos. Such research could clearly have far researching impact on treatment of human genetic diseases. The international community urgently needs to have a more detailed and comprehensive discussion on the ethical concerns and how to regulate this kind of research to ensure this kind of research instead of calling for a blanket moratorium. Chinese scientists are already taking part in the conversation going on in the international communities, given the many extensive collaborations with overseas institutions. We previously reviewed the extensive collaboration of BGI with their overseas partners and the implications on the standard research practice at BGI.25 It is also notable that many of these collaborative projects utilizes funding from the NIH and these institutions have to agree to abide by all relevant US laws and regulations, having signed a Federal Wide Assurance with OHRP. In China, as in other countries, there is a general willingness to conform to accepted international research practice. However, there are areas of controversy where there is no international agreement. As part of this ongoing vigorous international debate, regular conferences and workshops are conducted in China on bioethics with experts from all over the world to exchange ideas as part of collaborations with the NIH, other institutions in the US, Europe and other Asian countries. We certainly agree that the current regulations on governing research practices in China, as in other countries, are not perfect and stronger governance is needed. The starting point for the international debate should be that all countries can contribute with valuable policy lessons, rather than to frame the debate as a “Scientific and ethical divide between China and the West”.

Biographies Xiaomei Zhai is the Dean of School of Humanities and Social Sciences, Peking Union Medical College, in Beijing, PR China. Vincent Ng is Professor of Biology, Northern Virginia Community College, Woodbridge, Virginia, USA. Reidar Lie is Head of the Department of Philosophy, University of Bergen, Norway and Adjunct professor, School of Humanities and Social Sciences, Peking Union Medical College in Beijing, PR China.

24 UK scientists seek permission to genetically modify human embryos. Guardian September 18 2015. Available at: http://www.theguardian. com/science/2015/sep/18/uk-scientists-seek-permission-to-geneticallymodify-human-embryos [Accessed 8 Dec 2015]. 25 Op. cit., footnote 15.

No ethical divide between China and the West in human embryo research.

This is a discussion of the reaction to the recent research article publication in the journal Protein & Cell by a group of scientists at Sun Yat-sen ...
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