It is possible to modify human germline DNA by using CRISPR to edit the DNA of a human sperm, egg, or single-cell embryo. When used in conjunction with in vitro fertilization (IVF), gene-edited offspring are possible. Unlike somatic cells, if germline DNA is modified, the resulting genomic changes propagate to every cell of the body and to every cell of that person’s future offspring. Citing ethical concerns, including the permanent deleterious effects of potential errors in the germline editing process, the United Nations Educational, Scientific and Cultural Organization’s (UNESCO’s) International Bioethics Committee (IBC) in 2015 called for a global ban on editing the human germline.7 Nevertheless, at least one scientist has since said that he used CRISPR for germline-editing of children.8
Since the 1970s, the clinical application of IVF has generated many of the same ethical misgivings generated by CRISPR technology regarding its use for germline editing. In the U.S., IVF is extensively self-regulated by professionals but only marginally regulated by federal and state governments.9 Nevertheless, IVF currently facilitates more than 1% of births in the U.S. and presents acceptably limited known complications for the offspring.10 Comparing CRISPR technology to IVF, this Essay defends the ethicality of using CRISPR to repair germline mutations that cause serious congenital single-gene diseases. Accordingly, this Essay argues that the U.S. should not prohibit the use of CRISPR for such purposes.
Section I of this Essay recounts the history of CRISPR technology’s rapid advancement and the historically similar rise of IVF’s clinical applications. This section also briefly illustrates the resemblance between the ethical concerns that arose with the onset of IVF and those that are now posed by CRISPR. Section II of this Essay describes how the U.S. currently regulates clinical applications of CRISPR and IVF. This section illuminates the stark difference between the U.S. Food and Drug Administration’s (FDA’s) refusal to consider new drug applications for germline editing using CRISPR and its laissez-faire regulatory approach towards IVF. Section III analogizes the ethical considerations between CRISPR and IVF, including safety concerns, access inequality, public apprehension, and the potential rebirth of a eugenics movement. This section provides support for the argument that using CRISPR in conjunction with IVF for therapeutic purposes, specifically to repair hereditable mutations that cause serious congenital single-gene diseases, poses even fewer ethical challenges than IVF generally. The conclusion emphasizes that, based on this argument, the U.S. should not heavily restrict clinical applications of germline editing using CRISPR.
I. Human Germline Editing and IVF
A. The Rise of Clinical Germline Editing with CRISPR
In 2012, Jennifer Doudna, a professor of Molecular and Cell Biology at the University of California, Berkeley,11 published foundational research describing how to harness CRISPR to remove, edit, or replace any sequence of DNA in living organisms by customizing CRISPR sequences to complement and target the DNA of interest.12 Within 14 months, another cohort perfected the procedure to modify DNA in human cells so that such DNA modifications could treat or even cure human genetic diseases.13
These findings unleashed a biological revolution. CRISPR-related funding from the National Institute of Health (NIH) grew from $5 million in FY2011 to more than $1.1 billion in FY2018, and the number of related scientific publications grew from 87 in 2011 to almost 13,000 from 2011–2018.14 The projected global market for related technologies is projected to exceed $8 billion by 2025.15 While CRISPR technology may be used as a gene therapy to treat DNA mutations in adult somatic cells, it may also be used in conjunction with IVF to modify germline DNA to correct a harmful genetic mutation or to confer disease resistance.16 For example, CRISPR technology might be employed to repair the single-gene mutation that causes Huntington’s Disease.17 If repaired in the germline, the faulty gene responsible for Huntington’s Disease will not be present in the fetus, nor will it pass on to the future offspring of that child. Using CRISPR to edit the human germline permanently alters the human gene pool, and therefore such use raises ethical questions addressing the relative risks and benefits.18 Despite a statement by the Organizing Committee for the International Summit on Human Gene Editing that “it would be irresponsible to proceed with any clinical use . . . unless and until (i) the relevant safety and efficacy issues have been resolved . . . and (ii) there is broad societal consensus about the appropriateness of the proposed application,”19 at least one rogue scientist ignored the advisory and is reported to have successfully created germline-edited babies using CRISPR technology.20 Chinese Scientist Dr. He Jiankui (Dr. He) “sent a thunderbolt through the scientific world”21 when he publicized that he had used CRISPR on two human embryos to introduce a gene mutation that provides the children with resistance to HIV infection.22 Dr. He’s announcement earned him worldwide condemnation.23 In light of Dr. He’s actions, prominent researchers, including Eric Lander, founding director of the Broad Institute and former co-chair of the President’s Council of Advisors on Science and Technology, published an article in March 2019 advocating for a five-year global moratorium on hereditable genome editing.24 That still has not stopped doctors and scientists from preparing its clinical use; for example, Russian scientist Denis Rebrikov said he wished to carry out a clinical treatment like the one that Dr. He performed as well as another treatment that could prevent an inherited form of deafness.25
B. The Rise of Clinical Applications of IVF
The origin story of IVF shares many parallels to that of CRISPR. IVF is the process whereby an ovum is manually fertilized with sperm and the resulting embryo is implanted into a woman’s uterus to establish a pregnancy.26 Like CRISPR, IVF received enormous media attention. In 1978, the successful birth of the first IVF baby, Louise Brown, was described as the “medical media event of the year.”27 Just like CRISPR, the IVF industry generated rapid and continual market growth. By 2018, over 8 million babies had been born using IVF.28 The global IVF market generated $12.5 billion in 2018 and is expected to generate $25.6 billion by 2026.29 And like CRISPR, IVF’s first clinical use carried with it uncertain genomic consequences and considerable public apprehension. The safety considerations and ethical dilemmas surrounding its use were largely the same as those currently presented by CRISPR for human germline editing. In 1979, following Louise Brown’s birth, the Department of Health, Education and Welfare (HEW) and its Ethics Advisory Board (EAB) undertook a study of “the scientific, ethical, legal, and social issues surrounding human [IVF] . . . .”30 The 1979 EAB Report highlighted many of the same concerns expressed in opposition to germline editing using CRISPR, including “[t]he moral status of the embryo,” “questions of safety,” and progression towards “more objectionable procedures.”31 Just as scientists, bioethicists, and organizations today call for a moratorium on germline editing using CRISPR, the Journal of the American Medical Association printed an editorial in 1972 that similarly called for a moratorium on the clinical use of IVF.32 Nevertheless, IVF now facilitates roughly one in every 100 births in the U.S. and presents acceptably limited complications for the offspring.33 In the U.S., IVF is largely self-regulated by professionals, with more limited regulation by federal and state governments.34
II. Legal Landscape
A. CRISPR Regulation
Although there is no explicit federal law that directly prohibits human germline modification, there are some federal restrictions. Both the Novel and Exceptional Technology Research Advisory Committee (NExTRAC) at the National Institutes of Health (NIH) and the Center for Biologics Evaluation and Research (CBER) at the FDA govern the policy on experimental research and clinical application, respectively, of CRISPR technology in human cells.35 NExTRAC is a new federal advisory committee that serves as a “board for public discussion and advice on the scientific, safety, ethical, legal, and social issues associated with emerging biotechnologies” such as CRISPR.36
Whereas the NIH governs only federally funded, but not privately funded, research, the FDA regulates all clinical applications in interstate commerce, regardless of funding source.37 Therefore, the FDA is the primary regulatory barrier to widespread clinical germline editing using CRISPR. The FDA “is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.”38 The FDA has stated that “[n]ucleic acids or viruses used for human gene therapy will be subject to the same requirements as other biological drugs,”39 and that it “considers any use of CRISPR/Cas9 gene editing in humans to be gene therapy.”40 The CBER regulates gene therapy clinical studies, and researchers conducting such studies must submit an investigational new drug application (IND) prior to initiation.41 A therapy that employs CRISPR technology on human somatic cells must then proceed through the typical three-phase clinical trial process to receive approval from the FDA.42
Currently, however, the FDA is not authorized to consider applications that employ CRISPR technology in germline cells. Congress, on multiple occasions, has renewed an indirect ban on the use of CRISPR technology for clinical germline editing.43 The most recent legislation continues a blanket denial for the FDA to review any clinical trial application that would employ intentional genetic alterations to an embryo. Section 740 of the Consolidated Appropriations Act of 2021 provides:
None of the funds made available by this Act may be used to notify a sponsor or otherwise acknowledge receipt of a submission for an exemption for investigational use of a drug or biological product . . . in research in which a human embryo is intentionally created or modified to include a heritable genetic modification. Any such submission shall be deemed to have not been received by the Secretary, and the exemption may not go into effect.44
Despite Congress’s seeming attempt to constrain reckless human gene editing, “do it yourself” CRISPR kits are sold across the U.S. and could be used for self-administration.45 California is the first and only state to enact a law regulating CRISPR because of remaining “concerns . . . about the impact on consumer safety and public health.”46 The law states that “a person shall not sell a gene therapy kit . . . unless the seller includes a notice . . . in plain view and readily legible, stating that the kit is not for self-administration.”47
As discussed in Section II.B, the FDA conducts far less governance over IVF’s market presence than it does for CRISPR therapeutics.
B. IVF Regulation
Federal regulation of the IVF process is minimal. Practically, the Centers for Disease Control and Prevention (CDC) plays the largest role in IVF’s federal regulation. Pursuant to the Fertility Clinic Success Rate and Certification Act of 1992, laboratories conducting IVF must acquire certification by a laboratory accreditation program and must report pregnancy success rates to the CDC.48 The FDA has only marginal jurisdiction over IVF, regulating the drugs, biological products, and medical devices that are used during IVF treatment.49 State regulation is also meager; states that regulate IVF do so simply to ensure that labs are accredited and that IVF is covered by insurers.50 Professional and industry groups conduct most of IVF’s regulation. The American Society for Reproductive Medicine (ASRM) publishes practice guidelines as well as ethics committee reports and statements.51 Although not required, U.S. clinics may become members of the Society for Assisted Reproduction (SART) if they meet ethics and practice guidelines and accreditation standards.52
III. Comparing the Ethical Considerations Between CRISPR and IVF
A. Safety Risks to the Offspring: Genomic Off-Target Effects and Unintended Consequences
The FDA states that “for a drug to be approved for marketing, [the] FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients.”53 Factors that the FDA considers in this benefit-risk analysis include “the severity of the underlying condition and how well patients’ medical needs are addressed by currently available therapies [and] uncertainty about how the premarket clinical trial evidence will extrapolate to real-world use of the product in the postmarket setting.”54
The most commonly cited safety concern for using CRISPR to edit the human germline is off-target mutations and unknown effects.55 Once the germline has been altered, that modification will propagate to the genomes of all future generations. A poorly engineered CRISPR creates the risk that it will bind to the wrong genomic target instead (or bind to both the correct target and an unintended target) and thereby unintentionally and permanently alter the wrong gene.56 For example, one study conducted on human cells in 2013 found that CRISPR-associated off-target genes were “mutagenized with frequencies comparable to (or higher than) those observed at the intended on-target site.”57 In other words, CRISPR unintentionally modified DNA at the wrong spots about as often as it modified the targeted DNA. Another 2014 study using CRISPR-Cas9 to target the same CCR5 gene that Dr. He targeted in his clinical application found that two other sites in the genome were unintentionally cleaved.58 Because germline editing using CRISPR might elicit a mutation that is far worse than the one it seeks to eliminate, in many cases the potential risks of using the technology may outweigh the benefits.
Like CRISPR, the genomic effects of IVF during its early use were unknown, largely due to the limited understanding of the genome at the time.59 The 1978 Ethics Advisory Board collected thousands of public communications with arguments supporting and opposing the clinical application of IVF.60 Many people insisted “that more should be known about the probability of producing defective embryos” and that it would be “unethical . . . [to] support IVF and embryo transfer in humans before the risks and benefits have been more fully evaluated.”61 Many studies conducted during the 1970s had raised concerns over the risks to IVF offspring. For example, superovulation, the routine process of inducing a woman to release eggs, was found to be correlated with chromosomal abnormalities in the embryo.62 Additionally, the use of routine freezing techniques to preserve gametes or embryos was purported to produce mutations.63 Even within this past decade, researchers discovered that IVF offspring have increased epigenetic modifications, which are heritable changes in the genomic expression that are not related to mutated DNA sequences.64 Nevertheless, more recent epidemiological studies show that the long-term outcome for IVF offspring generally displays normal physical and neurological development and physical health.65 Perhaps resolving this paradox, only months ago, researchers have found that the epigenetic modifications in IVF offspring largely resolve by adulthood.66 The ever-changing state of our current understanding of the risks associated with new therapeutics demonstrates that we can never be wholly confident in the safety of any given therapy. It is likely that if scientists and doctors in the 1970s and 80s had had the ability to identify the epigenetic abnormalities associated with IVF offspring, they would have advised that the projected risks associated with such genomic irregularities to the IVF offspring and its progenies would invalidate the use of IVF altogether. As technological progressions allow scientists to identify new risks that previously were not even on the radar, it is important to bear in mind that the long-term putative effects associated with those risks often do not materialize, as exemplified by IVF.
Therefore, for the purposes of regulation, when weighing the risks associated with germline editing using CRISPR, in addition to quantifying the observable risks, careful attention should be placed on evidence of the therapy’s actual materialized effects or lack thereof. During the House Committee on Appropriations (COA) debate leading to the 2019 Consolidated Appropriations Act restrictions, Representative Robert Brown Aderholt (R-AL) (Aderholt) stated that “the ethics hadn’t caught up with the science, and quite honestly, the science hasn’t even caught up with the science.”67 Aderholt warned that what could be passed on could be “far worse.”68 However, Aderholt’s apprehensions are exaggerated. Since the 2013 and 2014 studies, many animal studies have shown that through careful design, improved CRISPR specificity can reduce or eliminate detectable levels of off-target mutations69 and show no statistically distinguishable difference from naturally occurring spontaneous mutations.70 Similarly, these studies found that CRISPR editing caused no observable physical effects different from the nonedited animals.71 Moreover, in one of these studies, researchers had even targeted two genes with different sequences that required two separate CRISPR constructs, thereby potentially doubling the likelihood of off-target effects.72
As to targeting single-gene diseases, the risks of off-target effects are even lower than for diseases that are more genetically complex. In such cases, the known risk of leaving the germline unmodified and allowing the disease to manifest should be calculated as higher than the potential risk of correcting that gene using CRISPR. Moreover, the risk of passing on harmful genetic mutations to offspring with CRISPR in such cases would be lower than that of a regular smoker;73 or of an older male, whose sperm mutation rate has been estimated to “doubl[e] every 16.5 years and increase[e] by 8-fold in 50 years.”74 Regulators should put into perspective that germline editing using CRISPR appears to present even fewer safety concerns for an embryo than smoking or aging. Animal studies should allay fears regarding existing uncertainty as to the actual long-term effects of CRISPR editing on the human germline.
B. Inequality of Access
An important ethical concern when allowing germline editing using CRISPR is the likelihood of unequal access to the technology. Similar accessibility concerns still exist regarding IVF, and they have been categorized by (1) the equality of access to IVF and (2) the equality issues raised by trait-selection practices.75
The cost of IVF is the factor that most affects equality of access to the technology.76 Because the average patient must undergo several IVF cycles for a successful birth, the cumulative average cost of IVF reaches $60,000.77 Although employee benefits or health insurance may cover at least part of that cost, the high price of IVF poses a serious barrier for the economically underprivileged to benefit from the technology.78 Nevertheless, countries may cover infertility treatment, including IVF, through a national health program; for example, Israel provides “free, unlimited IVF procedures for up to two ‘take-home babies’ until a woman is 45” years old.79 Unlike IVF, CRISPR alone does not present as high of a cost barrier; for example, effective July 2019, the Yale Genome Editing Center advertised guaranteed rates of between $9,500 and $12,000 for CRISPR-Cas9 gene modification.80 Developers of CRISPR expect the technology to greatly impact low-income countries.81 Nevertheless, when used for germline editing, CRISPR may only be used in conjunction with IVF, and therefore the combined treatment will exceed the cost of IVF treatment alone. Regulating CRISPR for germline editing, but not IVF, simply because of unequal access due to its marginal expense would be incongruent. Some might argue in favor of limiting the clinical availability of CRISPR as they have for IVF until such equality gaps are neutralized.82 However, according to that line of logic, no treatment should be fully accessible to anyone unless it is reasonably accessible to everyone. Surely the means of achieving widespread therapeutic access is not by banning the practice altogether. Besides, depriving an existing therapy or medical procedure to one simply because it is unavailable to another raises moral questions. As Representative Nita Lowey (D-NY) put it during the COA debate, “while some may feel a moral obligation to oppose [germline editing], others of us feel that we have a moral obligation to allow advances in science so fewer parents will have to watch a child die of a heritable disorder and to help eradicate terrible deadly diseases that can be passed down from generation to generation.”83 Instead of limiting clinical use of CRISPR to prevent unequal access altogether, society should focus on how to increase, not decrease, global access to the therapy.
The second category of equality issues includes those raised by trait-selection practices. Preimplantation genetic testing (PGT) may be used to determine the genetic characteristics or diseases following IVF but before implantation.84 A parent may choose a particular embryo or terminate a pregnancy based on the presence or absence of a particular genetic trait. If these practices increase in frequency and certain traits disappear among the population, people with those traits are likely to become increasingly marginalized and stigmatized. Adrienne Asch, a prominent bioethics scholar and strong advocate for disability justice, wrote that “researchers, professionals, and policymakers, who uncritically endorse testing followed by abortion, act from misinformation about disability, and express views that worsen the situation for all people who live with disabilities now or in the future.”85 Contrary to such concerns, some individuals affirmatively choose to have children with disabilities. In 2002, Candy McCullough and Sharon Duchesneau, a Maryland deaf couple, intentionally solicited a deaf sperm donor in order to have a deaf child.86 The case was not unique. One survey published in 2008 showed that three percent of 137 IVF clinics had used PGT “to select an embryo for the presence of a disability.”87 Bioethicist Silvia Camporesi has argued that the ethics of choosing an impairment through PGT should involve a balancing “between self-determination of parents within their sphere of reproductive freedom and their determination of future children” and “justice toward the future children. . . .”88 Camporesi argues that debating whether terms like “impairment” or “disability” are socially constructed is a fruitless endeavor because certain conditions, like deafness, whatever they are termed, impose a “limitation on the future of the child, and . . . a general hindrance for a vast array of plans of life.”89 Under this balancing test, Camporesi argues that it is unethical for a parent to employ PGT to affirmatively choose to have deaf offspring, as the general hindrance on life plans outweighs the parent’s self-determination interest.90 Under her balancing test, using CRISPR to treat a severe single-gene disease should be considered ethically defensible. Doing so poses no limits to the parents’ reproductive freedom and their determination of future children and doing so only reduces limitations of a reasonably broad array of different life plans for the children. The purpose of germline editing using CRISPR is to eliminate specific physical characteristics that limit the child’s major life activities, regardless of whether those limitations are defined as a “disability.”
C. Public Opinion Surveys
Scientists have proposed that “clinical germline editing should not proceed for any application without broad societal consensus. . . .”91 In 2018, the Associated Press-NORC Center for Public Affairs Research asked 1,067 adults in the U.S. if they support germline editing.92 While the majority of participants did oppose germline editing for “[a]ltering capabilities such as intelligence or athletic ability,” 65% supported germline editing for nonfatal hereditable conditions, such as blindness.93 For treating incurable diseases, such as Huntington’s disease, public support reached 71%.94 A similar 2018 Pew Research Center poll found similar results, that 72% of U.S. adults believed that treating a serious disease the baby would have at birth would be an appropriate use of CRISPR.95 Support for germline editing even for preventing nonfatal conditions garnered more support in 2018 than IVF enjoyed in 1978. In 1978, Gallup surveyed 2,684 adults in the U.S., only 60% of whom favored in vitro fertilization.96 A 1978 Harris survey that polled 1,501 American women also found that “majority opinion favor[ed] IVF.”97 In slight contrast to the Gallup poll, however, a majority of women wanted IVF prohibited until further testing had established its safety, and 50% also opposed federal funding of research on IVF.98 The argument that germline editing should be forbidden until a “societal consensus” in the U.S. is reached is obsolete. There is a greater societal consensus for germline editing using CRISPR now than there was for IVF in 1978. For the use of CRISPR to treat severe single-gene diseases, there is likely an even stronger consensus because the risks of off-target effects are reduced.
D. Genetic Enhancements and Eugenics
David Baltimore, a Nobel laureate in Physiology or Medicine, has expressed “concerns about initiating a ‘slippery slope’ from disease-curing applications toward uses with less compelling or even troubling implications.”99 Without clear boundaries separating gene therapy from other uses, we might risk reviving the eugenics movement of U.S. past. At the turn of the twentieth century, the American Breeder’s Association’s “Committee on Eugenics” was established “to investigate and report on heredity in the human race and to emphasize the value of superior blood and the menace to society of inferior blood.”100 Thirty-two states had eugenics programs that included schemes such as compulsory sterilizations.101 During the 2019 COA debate, Representative Jeffrey Lane Fortenberry (R-NE) argued that “if we cede . . . [our] framework of science and ethics to maverick bioengineers who are detached from larger societal considerations, the risks of harm are real. . . .”102 Representative Nita Lowey, who “reluctantly support[ed]” the inclusion of the amendment prohibiting the FDA to consider applications for clinical germline editing, said that while CRISPR could “reduce suffering and save lives,” she understands the apprehension that “gene editing can allow for unsettling genetic enhancements which may be against our values.”103 Scientists have warned that “[g]enetic enhancement could even divide humans into subspecies.”104
Similar fears were raised during the onset of IVF treatment. The 1979 EAB report found that many expressed a fear that if researchers or doctors consciously destroyed in vitro embryos, the practice “could lead to an inability to draw barriers to policies that allowed more obviously objectionable occasions for humans to end the life of other humans.”105 Specifically, “selective destruction of undesirable fertilized eggs might contribute to the creation of a eugenic program controlled by some officially condoned elite.”106 The report noted that people even feared that “barriers would fall to the creation of half-animal, half-human hybrids or chimeras.”107
In retrospect, such fears regarding IVF were overblown. Any residual doubt should be extinguished if germline editing is approved solely for therapeutics. For example, the FDA might allow new drug applications specifically for single-gene conditions that manifest into an existing congressionally defined standard of disability.108
Conclusion
Using CRISPR to repair germline mutations that cause serious congenital single-gene diseases is ethically justifiable. Such a use poses even fewer ethical barriers than does IVF generally, which is minimally regulated. Therefore, the COA erred in forbidding the FDA to even consider clinical germline editing applications.
For certain applications, modifying severe single-gene diseases in the germline using CRISPR would satisfy the FDA’s benefit-risk analysis. For example, where both parents will pass on the Huntington’s disease mutation to their children, CRISPR may be the only potential treatment to eliminate the mutation. Evidence also shows that public opinion strongly supports such use for CRISPR to address serious medical conditions or diseases. While equal access to the therapy poses an ethical concern, the answer is to enhance access, rather than to reject treatments that could eliminate serious physical or mental impairments that would substantially limit a child’s major life activities. Finally, fears of a new eugenics movement should be allayed if the FDA authorizes germline editing licenses only for therapies targeting severe single-gene diseases.
Endnotes
1. See Rodolphe Barrangou et al., CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes, 315 Science 1709 (2007).
2. See id.
3. See Ruud Jansen et al., Identification of Genes That Are Associated with DNA Repeats in Prokaryotes, 43 Molecular Microbiology 1565 (2002) (coining the term “CRISPR,” an acronym for Clustered Regularly Interspaced Short Palindromic Repeats). The researchers who conducted this investigation discovered and categorized these repetitive DNA or chemically related RNA sequences but had not yet identified their role in the organism.
4. See Feng Zhang et al., CRISPR/Cas9 for Genome Editing: Progress, Implications and Challenges, 23 Hum. Molecular Genetics R40 (2014); see also F. Ann Ran et al., Genome Engineering Using the CRISPR-Cas9 System, 8 Nature Protocols 2281 (2013).
5. See Ran et al., supra note 4; see also Janice S. Chen et al., Enhanced Proofreading Governs Crispr–Cas9 Targeting Accuracy, 550 Nature 407 (2017).
6. See Dianne Nicol et al., Key Challenges in Bringing CRISPR-Mediated Somatic Cell Therapy into the Clinic, 9 Genome Med. 85 (2017). Somatic cells are nonreproductive cells. Alterations in these cells “can affect the individual, but they are not passed on to offspring.” Somatic Cells, Nat’l Human Genome Rsch. Inst. (NHGRI), https://www.genome.gov/genetics-glossary/Somatic-Cells. Germline, or germ cells, are eggs and sperm that pass genes to the next generation. Germ Line, NHGRI, https://www.genome.gov/genetics-glossary/germ-line (last visited Apr. 14, 2020).
7. U.N. Educ., Sci. & Cultural Org., Int’l Bioethics Comm., Report of the IBC on Updating Its Reflection on the Human Genome and Human Rights 28 (2015) [hereinafter 2015 IBC Report].
8. See Dennis Normile, CRISPR Bombshell: Chinese Researcher Claims to Have Created Gene-Edited Twins, Science (Nov. 26, 2018, 1:10 PM), https://www.sciencemag.org/news/2018/11/crispr-bombshell-chinese-researcher-claims-have-created-gene-edited-twins; Ken Moritugu, China Convicts 3 Researchers Involved in Gene-Edited Babies, AP News (Dec. 30, 2019), https://apnews.com/article/health-scientific-research-china-genetics-he-jiankui-7bf5ad48696d24628e49254df504e3ee.
9. See Kristine S. Knaplund, Synthetic Cells, Synthetic Life, and Inheritance, 45 Val. U. L. Rev. 1361, 1368 (2011); see also Am. Soc’y for Reprod. Med., Oversight of Assisted Reproductive Technology, https://www.asrm.org/globalassets/asrm/asrm-content/about-us/pdfs/oversiteofart.pdf.
10. See Joseph Nordqvist, IVF: What Does It Involve?, Med. News Today (Feb. 5, 2018), https://www.medicalnewstoday.com/articles/262798; see generally Ctrs. for Disease Control & Prevention, 2017 Assisted Reproductive Technology Fertility Clinic Success Rates Report (2019), https://www.cdc.gov/art/reports/2017/fertility-clinic.html.
11. See Jennifer A. Doudna, Berkeley Rsch., https://vcresearch.berkeley.edu/faculty/jennifer-doudna.
12. See Martin Jinek et al., A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity, 337 Science 816 (2012).
13. See Ran et al., supra note 4, at 2281.
14. See Marcy E. Gallo et al., Cong. Rsch. Serv., R44824, Advanced Gene Editing: CRISPR-Cas9, at 8–9 (2018) [hereinafter 2018 CRS Report].
15. See Press Release, Grand View Rsch., Genome Editing Market Size Worth $8.1 Billion by 2025 (Feb. 2017), http://www.grandviewresearch.com/press-release/global-genome-editing-market.
16. See Nicol et al., supra note 6.
17. See Su Yang et al., CRISPR/Cas9-Mediated Gene Editing Ameliorates Neurotoxicity in Mouse Model of Huntington’s Disease, 127 J. Clinical Investigation 2719 (2017).
18. See, e.g., 2015 IBC Report, supra note 7, at 7–12.
19. Nat’l Acads. of Scis., Eng’g, & Med., Comm. on Sci., Tech., & L. Pol’y & Glob. Affs., Meeting in Brief, in International Summit on Human Gene Editing: A Global Discussion, at 7 (Nat’l Acads. Press 2015), https://www.nap.edu/read/21913/chapter/1.
20. See Normile, supra note 8.
21. Pam Belluck, Chinese Scientist Who Says He Edited Babies’ Genes Defends His Work, N.Y. Times (Nov. 29, 2018), https://www.nytimes.com/2018/11/28/world/asia/gene-editing-babies-he-jiankui.html.
22. See David Cyranoski & Heidi Ledford, International Outcry Over Genome-Edited Baby Claim, 563 Nature 607 (2018).
23. See, e.g., Alexandra Harney & Kate Kelland, China Orders Investigation After Scientist Claims First Gene-Edited Babies, Reuters (Nov. 26, 2018), https://www.reuters.com/article/us-health-china-babies-genes/china-orders-investigation-after-scientist-claims-first-gene-edited-babies-idUSKCN1NV19T; see also David Cyranoski & Heidi Ledford, How the Genome-Edited Babies Revelation Will Affect Research, Nature (Nov. 27, 2018), https://www.nature.com/articles/d41586-018-07559-8; Cyranoski & Ledford, supra note 22.
24. Eric S. Lander et al., Adopt a Moratorium on Heritable Genome Editing, 567 Nature 165, 168 (Mar. 14, 2019) (“Governments would publicly declare that they will not permit any clinical use of human germline editing for an initial period of fixed duration. Five years might be appropriate.”); see Eric S. Lander, Broad Inst., https://www.broadinstitute.org/bios/eric-s-lander. Interestingly, although many pioneers of CRISPR technology co-authored this article, Doudna was not one of them.
25. Rob Stein, A Russian Biologist Wants to Create More Gene-Edited Babies, NPR (June 21, 2019), https://www.npr.org/sections/health-shots/2019/06/21/733782145/a-russian-biologist-wants-to-create-more-gene-edited-babies.
26. In Vitro Fertilization (IVF), Mayo Clinic (June 22, 2019), https://www.mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716.
27. Knaplund, supra note 9, at 1364 (quoting Daniel Callahan, In Vitro Fertilization: Four Commentaries, Hastings Ctr. Rep., Oct. 1978, at 7).
28. European Soc’y of Hum. Reprod. & Embryology, More Than 8 Million Babies Born from IVF Since the World’s First in 1978, Sci. Daily (July 3, 2018), https://www.sciencedaily.com/releases/2018/07/180703084127.htm.
29. Surabhi Pandey & Onkar Sumant, IVF Services Market Outlook—2026, Allied Mkt. Rsch. (Oct. 2019), https://www.alliedmarketresearch.com/IVF-in-vitro-fertilization-services-market.
30. Protection of Human Subjects; HEW Support of Human In Vitro Fertilization and Embryo Transfer: Report of the Ethics Advisory Board, 44 Fed. Reg. 35,033, 35,034 (June 18, 1979) [hereinafter 1979 EAB Report].
31. Id. at 35,052.
32. Editorial, Genetic Engineering in Man: Ethical Considerations, 220 J. Am. Med. Ass’n 721 (May 1, 1972).
33. See Nordqvist, supra note 10; see generally Ctrs. for Disease Control & Prevention, supra note 10.
34. See Knaplund, supra note 9, at 1368; see also Am. Soc’y for Reprod. Med., supra note 9.
35. See Development & Approval Process (CBER), U.S. Food & Drug Admin. (Mar. 28, 2019), https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber; Amendments to Streamline Review of Gene Therapy Trials and Transform the RAC to NExTRAC, Nat’l Insts. Health (Apr. 2019), https://osp.od.nih.gov/biotechnology/nih-guidelines/. The FDA regulates the approval and sale of CRISPR-related drugs and therapeutics. CRISPR research is subject to oversight by the CBER.
36. Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), 84 Fed. Reg. 17,858, 17,861 (Apr. 26, 2019). NExTRAC’s establishment replaced the Recombinant DNA Advisory Committee (RAC), which provided duplicative oversight regarding gene therapies, like CRISPR technology. Id. at 17,860. The NIH hosted the inaugural meeting of NExTRAC on December 5–6, 2019, and the meeting topics included “gene editing in the clinic.” Agenda, NExTRAC, Nat’l Insts. of Health (Dec. 5, 2019), https://osp.od.nih.gov/wp-content/uploads/NExTRAC_Dec_2019_Agenda.pdf.
37. Comm. on the Indep. Rev. & Assessment of the Activities of the NIH Recombinant DNA Advisory Comm., Inst. Med., Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee 41–76 (Nat’l Acads. Press 2014).
38. What We Do, U.S. Food & Drug Admin., https://www.fda.gov/about-fda/what-we-do (last visited Apr. 14, 2020).
39. Statement of Policy for Regulating Biotechnology Products, 51 Fed. Reg. 23,310, 23,311 (June 26, 1986).
40. Information About Self-Administration of Gene Therapy, U.S. Food & Drug Admin. (Nov. 21, 2017), https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/information-about-self-administration-gene-therapy.
41. See 21 C.F.R. §§ 312.20, 312.23; Investigational New Drug Applications (INDs) for CBER-Regulated Products, U.S. Food & Drug Admin., https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/investigational-new-drug-applications-inds-cber-regulated-products.
42. 21 C.F.R. § 312.21.
43. The language first appeared in the Consolidated Appropriations Act of 2016, Pub. L. No. 114–113, § 749, 129 Stat. 2242, 2283 (2015), and has been renewed yearly. As to federally funding experimental research, although the NIH Guidelines in prior years stated that the Recombinant DNA Advisory Committee “will not . . . entertain proposals for germ line alteration,” that refusal is not present in the 2019 report. Compare Francis S. Collins, Dir., Nat’l Insts. of Health, Statement on NIH Funding of Research Using Gene-Editing Technologies in Human Embryos, Nat’l Insts. Health (Apr. 28, 2015), https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using-gene-editing-technologies-human-embryos (stating the above), with NIH Guidelines, supra note 36, 84 Fed. Reg. 17,858 (making no such statement).
44. Consolidated Appropriations Act of 2021, Pub. L. No. 116–260, § 740, 134 Stat. 1182, 1225 (2020).
45. See Elizabeth Fernandez, Yes, People Can Edit the Genome in Their Garage. Can They Be Regulated?, Forbes (Sept. 19, 2019), https://www.forbes.com/sites/fernandezelizabeth/2019/09/19/yes-people-can-edit-the-genome-in-their-garage-can-they-be-regulated/. The FDA has explicitly stated that the sale of these kits is illegal. See Information About Self-Administration of Gene Therapy, supra note 40.
46. 2019 Cal. Legis. Serv. ch. 140, § 1(d) (S.B. 180) (West).
47. Cal. Bus. & Prof. Code § 22949.50.
48. Fertility Clinic Success Rate and Certification Act of 1992, Pub. L. No. 102-493, §§ 2–3, 106 Stat. 3146 (codified at 42 U.S.C. §§ 263a-1, 263a-2).
49. See FDA Obstetrical and Gynecological Devices, 21 C.F.R. §§ 884.1, 884.6100–.6200.
50. See, e.g., Cal. Health & Safety Code §§ 1248.15, 1374.55; Cal. Ins. Code § 10119.6.
51. See Publications Overview, Am. Soc’y for Reprod. Med., https://www.asrm.org/news-and-publications/publications-overview/ (last visited Apr. 14, 2020).
52. See What Is SART?, Soc’y for Assisted Reprod. Tech., https://www.sart.org/patients/what-is-sart/ (last visited Apr. 14, 2020).
53. U.S. Food & Drug Admin., Benefit-Risk Assessment in Drug Regulatory Decision-Making 3 (2018), https://www.fda.gov/files/about%20fda/published/Benefit-Risk-Assessment-in-Drug-Regulatory-Decision-Making.pdf.
54. Id.
55. See, e.g., Lander et al., supra note 24.
56. Josh Tycko et al., Methods for Optimizing CRISPR-Cas9 Genome Editing Specificity, 63 Molecular Cell 355, 363 (2016).
57. Yanfang Fu et al., High-Frequency Off-Target Mutagenesis Induced by CRISPR-Cas Nucleases in Human Cells, 31 Nature Biotech. 822 (Sept. 2013) [hereinafter 2013 study].
58. Yanni Lin et al., CRISPR/Cas9 Systems Have Off-Target Activity with Insertions or Deletions Between Target DNA and Guide RNA Sequences, 42 Nucleic Acids Rsch. 7473, 7473–74 (2014) [hereinafter 2014 study].
59. Laurence E. Karp & Roger P. Donahue, Preimplantational Ectogenesis: Science and Speculation Concerning In Vitro Fertilization and Related Procedures, 124 W. J. Med. 282, 295–96 (Apr. 1976).
60. See 1979 EAB Report, supra note 30, 44 Fed. Reg. at 35,051.
61. Id. at 35,052.
62. Joelle G. Boué & André Boué, Increased Frequency of Chromosomal Anomalies in Abortions After Induced Ovulation, 301 Lancet 679 (Mar. 24, 1973). Such concerns were particularly significant given that “[s]uperovulation ha[d] become a routine medical therapy used for . . . in vitro fertilization.” Stephanie A. Beall & Alan Decherney, The History and Challenges Surrounding Ovarian Stimulation in the Treatment of Infertility, 97 Fertility & Sterility 795, 795 (Apr. 2012).
63. Lynn R. Fraser et al., Increased Incidence of Triploidy in Embryos Derived from Mouse Eggs Fertilised In Vitro, 260 Nature 39 (Mar. 4, 1976). Similar to superovulation, identifying the safety risks of cryopreservation was important because “[h]uman embryo cryopreservation [was] an indispensable extension of in-vitro fertilization.” Jacqueline Mandelbaum et al., Cryopreservation in Human Assisted Reproduction Is Now Routine for Embryos but Remains a Research Procedure for Oocytes, 13 Human Reprod. 161, 161 (Supp. 3 1998).
64. See Asli Uyar & Emre Seli, The Impact of Assisted Reproductive Technologies on Genomic Imprinting and Imprinting Disorders, 26 Current Op. Obstetrics & Gynecology 210 (June 2014).
65. Yue-hong Lu et al., Long-Term Follow-up of Children Conceived Through Assisted Reproductive Technology, 14 J. Zhejiang Univ. 359, 362–65 (2013).
66. Boris Novakovic et al., Assisted Reproductive Technologies Are Associated with Limited Epigenetic Variation at Birth That Largely Resolves by Adulthood, 10 Nature Commc’ns art. 3922, at 9 (Sept. 2, 2019).
67. Full Committee Markup of FY2020 Transportation-Housing & Urban Development, Agriculture-Rural Development-Food and Drug Administration, House Comm. on Appropriations, at 2:36:22 (June 4, 2019), https://appropriations.house.gov/events/markups/fy2020-transportation-housing-urban-development-and-related-agencies-appropriations [hereinafter 2019 COA debate].
68. Id. at 2:53:03.
69. Yangang Fu et al., Improving CRISPR-Cas RNAs, 32 Nature Biotech. 279 (2014).
70. Yan Dong et al., Genome-wide Off-Target Analysis in CRISPR-Cas9 Modified Mice and Their Offspring, 9 G3: Genes, Genomes, Genetics 3645 (2019).
71. Id.
72. Id.
73. Joost O. Linschooten et al., Paternal Lifestyle as a Potential Source of Germline Mutations Transmitted to Offspring, 27 Faseb J. 2873, 2877 (2013).
74. Augustine Kong et al., Rate of De Novo Mutations and the Importance of Father’s Age to Disease Risk, 488 Nature 471, 472 (Aug. 23, 2012).
75. Mary Crossley, Dimensions of Equality in Regulating Assisted Reproductive Technologies, 9 J. Gender Race & Just. 273, 274 (2005).
76. William Ombelet, Global Access to Infertility Care in Developing Countries: A Case of Human Rights, Equity and Social Justice, 3 Facts, Views & Vision in ObGyn 257–66 (2011).
77. Susannah Snider, How Much Does IVF Cost? And How Can I Pay for It?, U.S. News (Aug. 27, 2019), https://money.usnews.com/money/personal-finance/spending/articles/how-much-does-ivf-cost-and-how-can-i-pay-for-it.
78. Id.
79. Dina Kraft, Where Families Are Prized, Help Is Free, N.Y. Times (July 17, 2011), https://www.nytimes.com/2011/07/18/world/middleeast/18israel.html.
80. See Fees, Yale Genome Editing Ctr., Yale Sch. of Med., https://medicine.yale.edu/compmed/ags/fees/ (last visited Apr. 14, 2020).
81. Amy Maxmen, Faster, Better, Cheaper: The Rise of CRISPR in Disease Detection, 566 Nature 437 (2019).
82. See Crossley, supra note 75, at 279–80.
83. 2019 COA debate, supra note 67, at 2:46:23.
84. The term PGT includes preimplantation genetic diagnosis and preimplantation genetic screening, which are methods to test embryos for genetic abnormalities before implantation. See Preimplantation Genetic Testing, ReproductiveFacts.org (2014), https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/preimplantation-genetic-testing/.
85. See Adrienne Asch, Disability Equality and Prenatal Testing: Contradictory or Compatible?, 30 Fla. State Univ. L. Rev. 315, 316–17 (2003). Asch held this viewpoint despite her pro-choice stance. Id. at 317 n.6.
86. M. Spriggs, Lesbian Couple Create a Child Who Is Deaf Like Them, 28 J. Med. Ethics 283 (2002).
87. Susannah Baruch et al., Genetic Testing of Embryos: Practices and Perspectives of U.S. In Vitro Fertilization Clinics, 89 Fertility & Sterility 1053, 1054–55, 1056 fig.1 (2008).
88. Silvia Camporesi, Choosing Deafness with Preimplantation Genetic Diagnosis: An Ethical Way to Carry on a Cultural Bloodline?, 19 Cambridge Q. Healthcare Ethics 86, 86 (2010).
89. Id. at 93–94. Congress has similarly defined “disability” under the Americans with Disabilities Act of 1990 as including “a physical or mental impairment that substantially limits one or more major life activities . . . includ[ing] . . . caring for oneself, performing manual tasks, seeing, hearing, eating, sleeping, walking, standing, lifting, bending, speaking, breathing, learning, reading, concentrating, thinking, communicating, and working.” 42 U.S.C. § 12102(1)–(2).
90. Camporesi, supra note 88, at 93–94.
91. See Lander et al., supra note 24, at 167.
92. Human Genetic Engineering, AP-NORC, https://apnorc.org/projects/human-genetic-engineering/ (presenting results of AP-NORC poll conducted Dec. 13–16, 2018) (last visited Apr. 14, 2020).
93. Id.
94. Id.
95. Cary Funk & Meg Hefferon, Public Views of Gene Editing for Babies Depend on How It Would Be Used, Pew Rsch. Ctr. (July 26, 2018), https://www.pewresearch.org/science/2018/07/26/public-views-of-gene-editing-for-babies-depend-on-how-it-would-be-used/.
96. Heather Mason Kiefer, Gallup Brain: The Birth of In Vitro Fertilization, Gallup (Aug. 5, 2003), https://news.gallup.com/poll/8983/gallup-brain-birth-vitro-fertilization.aspx.
97. See 1979 EAB Report, supra note 30, 44 Fed. Reg. at 35,053.
98. Id.
99. David Baltimore et al., A Prudent Path Forward for Genomic Engineering and Germline Gene Modification, 348 Science 36 (2015).
100. W.D. Stansfield, The Bell Family Legacies, 96 J. Heredity 1, 2 (2005).
101. Kim Severson, Thousands Sterilized, a State Weighs Restitution, N.Y. Times (Dec. 9, 2011), https://www.nytimes.com/2011/12/10/us/redress-weighed-for-forced-sterilizations-in-north-carolina.html?_r=1&hp.
102. 2019 COA debate, supra note 67, at 2:43:23.
103. Id. at 2:45:20–2:47:48.
104. Lander et al., supra note 24, at 167.
105. 1979 EAB Report, supra note 30, 44 Fed. Reg. at 35,053.
106. Id.
107. Id.
108. See Americans with Disabilities Act of 1990, 42 U.S.C. § 12102(1)–(2).