Volume 9 Issue 1 CREIGHTON INTERNATIONAL AND COMPARATIVE LAW JOURNAL The Human Germline Modification Index: An International Risk Assessment for the Production of Genetically Modified Humans By: Jason Glanzer1 I. INTRODUCTION In 2015, the world scientific community was surprised by the announcement that a genetically modified human embryo was created in a Chinese laboratory.2 These modifications were germline in their effect, meaning that if the embryo matured into an adult, that person could have children that also carried the same genetic modifications.3 This experiment highlighted a breakthrough method recently developed in the field of molecular biology, the CRISPR-Cas9 system, which can modify genomes in living organisms for a fraction of the labor and cost of previous methods.4 Although not allowed to progress to a fully developed human, the experiment was marked by concern by many in the scientific world as possibly crossing a moral and ethical line, or at least as an experiment that was performed before proper regulatory guidelines were in place.5 In the months following the announcement, several scientific and international groups gathered to develop a consensus of what limitations should be placed on the production of germline modified humans (“GMHs”).6 Although consensus has not been reached for most specific issues relating to GMHs, most agreed that germline modification tools, such as CRISPR-Cas9, are 1 Jason Glanzer, PhD, J.D. Candidate, 2018, Creighton University School of Law. 2 See generally Puping Liang et al., CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes, 6 PROTEIN CELL 363 (2015) (This study is the first published study of a genetically modified human embryo). 3 Id. 4 Renjie Jiao & Caixia Gao, The CRISPR/Cas9 Genome Editing Revolution, 43 J. GENETICS AND GENOMICS 227, 227-28 (2016). 5 Kewal Krishan et al., Human Genome Editing and Ethical Considerations, 22 SCI. AND ENGINEERING ETHICS 597, 597-99 (2015). 6 John Travis, Germline editing dominates DNA summit, 350 SCI. 1299, 1299 (2015). 68 Volume 9 Issue 1 CREIGHTON INTERNATIONAL AND COMPARATIVE LAW JOURNAL currently not yet refined enough to risk experimentation on humans.7 However, as we saw in the last decade with human cloning in South Korea, general consensus on risk does not prevent rogue countries or laboratories from performing experiments that much of the world abhors.8 This is especially true with the current issue of GMHs, as CRISPR-Cas9 technology is particularly easy to use.9 Any country that has both modest capabilities for biotechnology and in-vitro fertilization (“IVF”) clinic is capable of producing GMHs.10 For these countries, regulations that prohibit GMH production are extremely important and should “be required to express preventive measures against abuses of germline genome editing.”11 Araki et al., has tracked GMH regulation in 39 mostly industrialized nations.12 Many countries with highly established biotech industries also have highly regulated guidelines regarding GMH production.13 However, countries with newly developing biotech capabilities have not been similarly tracked.14 To discern which countries are at risk for producing GMHs, the present article submits a Human Germline Modification Index (“HGMI”) that tracks what countries have the capability of producing GMHs, and whether or not they also have regulatory control over these processes.15 The article begins by providing a background on the discovery of the CRISPR-Cas9 system, its modification for use in animals and the relative ease by which this technology can be used on humans.16 Upon this foundation, the article describes how each criterion for the HGMI was 7 Committee on Science, Technology, and Law, Policy and Global Affairs, National Academies of Sciences, Engineering, and Medicine, International Summit on Human Gene Editing: A Global Discussion, 44-45 (Steven Olson, 2015). 8 Gina Kolata, Cloning Creates Human Embryos, N.Y. TIMES, Feb. 12, 2004. 9 Masahito Watanabe & Hiroshi Nagashima, Genomic Editing of Pig, 1630 METHODS IN MOLECULAR BIOLOGY 121, 121 (2017). 10 See Motoko Araki & Tetsuya Ishii, International regulatory landscape and integration of corrective genome editing into in vitro fertilization, 12 REPROD. BIOLOGY AND ENDOCRINOLOGY 1, 2 (2014) (CRISPR is a rapidly developing technology that is relatively easy to implement, and can be added to an IVF protocol). 11 Id. at 10. 12 Id. at 8. 13 See Id. 14 See generally Id. (Araki’s list of 39 countries are for the most part all industrialized. Most non- industrialized countries have not been tracked). 15 See infra note 54. 16 See infra notes 19-27. 69 Volume 9 Issue 1 CREIGHTON INTERNATIONAL AND COMPARATIVE LAW JOURNAL researched and quantified.17 Finally, the article gives an in-depth look at four countries that scored highest in the HGMI: Iran, Malaysia, Taiwan, and the Philippines.18 II. BACKGROUND A. CRISPR-CAS9: AN INTRODUCTION Before its modification for use in animals, CRISPR-Cas9 was initially discovered as a defense system that allows bacteria to protect themselves from assault by viruses.19 If a viral genome is exposed when invading a bacterium, some bacteria are capable of cutting out a small piece of the viral DNA and pasting it within the bacterium’s own genome, in a region specifically defined as having clustered, regularly interspaced short palindromic repeats, which is the basis for the anagram, ‘CRISPR’.20 The bacterium then creates a single-stranded RNA containing the viral sequence, and using the Cas9 endonuclease, an enzyme produced by bacteria that cuts DNA, searches throughout bacterium, looking for any DNA that also contains the viral sequence.21 When viral DNA that matches this sequence is found, The Cas9 endonuclease cleaves the viral genome, rendering the virus unable to replicate.22 Scientists have adapted CRISPR-Cas9 for use in eukaryotic systems, allowing researchers to synthesize custom RNA molecules that can target specific regions within animal genomes.23 The targeting RNA can be injected into embryonic cells, where they find and cleave the DNA.24 Synthetic DNA of the corrected sequence is also injected into the cell, and is picked up by the cell’s own DNA repair proteins and used to patch the cleaved DNA, creating a genetically modified 17 See infra notes 56-85. 18 See infra notes 92-124. 19 Rodolphe Barrangou, CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes, 315 SCI. 1709, 1709-10 (2007); Rimantas Sapranauskas, The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli, 39 NUCLEIC ACIDS RES. 9275, 9275 (2011). 20 Barrangou, supra note 19, at 1710-12. 21 Sapranauskas supra note 19, at 9275-76. 22 Martin Jinek et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity, 337 SCI. 816, 816 (2012). 23 Daisuke Mashiko et al., Feasibility for a large scale mouse mutagenesis by injecting CRISPR/Cas plasmid into zygotes, 56 DEV. GROWTH AND DIFFERENTIATION 122, 123 (2014). 24 Id. at 122-23. 70 Volume 9 Issue 1 CREIGHTON INTERNATIONAL AND COMPARATIVE LAW JOURNAL cell.25 Animals are diploid creatures, having two copies of every gene.26 CRISPR-Cas9 is capable of modifying both copies of a targeted animal gene at once, which is a great improvement over traditional methods where only one copy can be targeted each generation.27 B. BANNING GMHS: A BIOLOGICAL ARGUMENT Although CRISPR-Cas9 is highly efficient in targeting and modifying genes in mammalian embryos, it is not perfect, and currently is prone to having activity at off-target sites.28 As only three percent of the human genome is used for coding proteins, it is likely that a CRISPR-Cas9 modified human born with a few off-target modifications would not look any different than the general population or have any genetic diseases.29 For couples that are both homolozygous recessive for the same genetic disease, such as hemophilia, CRISPR-Cas9 would likely allow them to have a child free from their disease.30 However, the small, off-target mutations in the child would live on and be transferred to their children.31 If CRISPR-Cas9 is widely used, while still having the problem of off-target modifications, there will be people with aggregations of these mutations in the future, which eventually may spawn new genetic problems and diseases, lowering the genetic health of the world population.32 This cataclysmic prediction has been echoed by other scientists.33 Thus, CRISPR-Cas9 can now 25 Id. at 124. 26 Anton Wutz, Haploid animal cells, 141 DEVELOPMENT 1423, 1423 (2014). 27 Andrew R. Bassett et al., Mutagenesis and homologous recombination in Drosophila cell lines using CRISPR/Cas9, 3 BIOLOGY OPEN 42, 42 (2014). 28 Liang et al., supra note 2, at 368. 29 Wojciech Makalowshi, The human genome structure and organization, 48 ACTA BIOCHIMICA POLONICA 587, 589 (2001). 30 See Tatjiana I Cornu et al., Refining strategies to translate genome editing to the clinic, 23 NATURE MED. 415, 416 (2017). 31 See Dana Carroll, A Perspective on the State of Genome Editing, 24 MOLECULAR THERAPY 412, 412 (2016) (discussing the current inadequacies in detecting and minimizing off-target effects of heritable modifications). 32 Michael McCarthy, Scientists Call for Moratorium on Clinical Use of Human Germline Editing, 351 BRITISH MED. J. h6603, 1 (2015). 33 Edward Lanphier et al., Don’t edit the human germline, 519 NATURE 410, 410-11 (2015). 71 Volume 9 Issue 1 CREIGHTON INTERNATIONAL AND COMPARATIVE LAW JOURNAL give a short-term benefit to couples trying to produce a healthy