AbstractCRISPR/Cas9 is a rapidly developing gene editing technology that will soon have many clinical applications. As with many other new technologies, somatic gene editing with CRISPR/Cas9 raises concerns about equitable access to therapies by historically disenfranchised racial and ethnic minorities. We describe justice concerns related to CRISPR/Cas9, including its potential impact on historically mistreated populations through underrepresentation of minorities in genomic databases and the potential for disparate access to somatic gene therapies when they become clinically available. We then describe ongoing work that aims to address these justice concerns. We conclude by highlighting important considerations to ensure equitable access to therapies going forward, including enhancing diversity in genomic sequencing efforts, improving education and transparency, and building partnerships with underserved and socially disenfranchised communities.
Gene editing has been possible for years with tools such as Zinc-finger nucleases and TALENs (transcription activator-like effector nucleases).1 CRISPR/Cas9 is one such adaptable and specific tool in which an RNA “guide” binds to a specific stretch of DNA and directs the Cas9 nuclease to introduce a cut in the genetic sequence. Other functional groups can be added to further alter the stretch of DNA.2,3 CRISPR/Cas9 has many potential clinical applications. The initial focus has been on cancer immunotherapy and correction of single gene disorders.4-6 For example, several teams have used the CRISPR/Cas9 system to correct pathogenic variants underlying beta thalassemia, a hemoglobinopathy.7 CRISPR/Cas9 offers multiple options to correct such defects, including changing the genetic code at the locus containing the pathogenic variant or creating an alternate hemoglobin product that can reduce severity of disease. With the advent of CRISPR/Cas9 come new considerations of when and how this technology should be applied in the clinical setting.
A key ethical distinction in discussions of human genome editing is that between germline applications (alterations that will be passed down to future generations) and somatic applications (those that will not be passed down),8 which is addressed in detail in the consensus report of the International Summit on Human Gene Editing.9 Germline editing is controversial because of ethical and clinical risks inherent in making a genetic change that would be inherited. Although the National Academies of Sciences, Engineering, and Medicine (NASEM) have recently begun to discuss criteria for ethical germline editing,10 most professional societies—including the NASEM, the American Society of Human Genetics, the European Society of Human Genetics, and the American College of Medical Genetics and Genomics—currently forbid germline gene editing.9,11-13 For this reason, this discussion will be limited to somatic gene editing only.
For CRISPR/Cas9 to be maximally beneficial to all communities—and to potentially mitigate, rather than exacerbate, health care disparities—equitable opportunities to participate in and benefit from research are paramount. This article will detail several barriers to equitable participation in and benefit from this kind of research and opportunities to overcome these barriers.
Barriers to Equitable Participation in and Benefit from Research
Mistrust of research. Minority groups in the United States have repeatedly experienced unequal and unethical treatment in research, ranging from participation without adequate informed consent to forced or coerced participation in treatments and studies. This mistreatment is perhaps most notable among African Americans in light of transgressions such as those in the US Public Health Service Tuskegee Syphilis Study, but numerous other groups have experienced similar mistreatment.14-16 Scars from this mistreatment still create mistrust of the medical and scientific community, as evidenced by low enrollment rates of African Americans and other minority groups in many research studies.14,17,18 Furthermore, minority communities are aware of health disparities and that they often receive inferior care compared to wealthier, nonminority groups.19,20 Concerns of minority groups in the US include unjust distribution of new resources and the potential for genetic enhancements to actually exacerbate disparities.21 These concerns must be addressed in the enrollment phase of new trials of CRISPR/Cas9 to ensure adequate representation of minority patients and adequate protection of these historically mistreated groups.
Underrepresentation in research. A second barrier to equitable participation in research is underrepresentation of minority patients in genetic databases that inform future research. While the National Institutes of Health (NIH) Human Genome Project and the United Kingdom’s 100,000 Genomes Project have expanded general knowledge of the human genome, overall there has been a lack of diversity in large-scale genome projects.22,23 Recent work estimates that only 3% of participants in genome-wide association studies (GWAS) published in the GWAS catalogue are of African descent.24,25 These studies are crucial for understanding associations between genetic variants and disease within specific populations. Without adequate understanding of the range of clinical variants, it will be harder to tailor therapies specifically to minority populations if less is known about their genomic makeup. Consequently, underrepresented minorities will likely miss out on potential gene therapy benefits.26
Disparate access to research benefits. Racial and ethnic minorities in the US have very disparate health outcomes and access to health care. In this country, socioeconomic status is strongly associated with race and ethnicity,27,28 raising concerns that the benefits of gene therapy will prove unavailable to some of the neediest groups for financial reasons.29,30 Gene therapy treatments might initially be funded through research, but these are likely to be prohibitively expensive for many once commercially available. When such new therapies are introduced to the market, minority populations are less likely to have access to them.31 Some of this inequity in access is hypothesized to be a result of overt or subconscious racism and differential treatment in medicine.17,32 There is likely also a disincentive to participate in research if potential participants perceive that benefits of research might not be available to them, although research is needed to support this hypothesis.
Taking Steps Forward
To overcome the aforementioned barriers to minorities’ participating in and benefiting from research, the scientific community must ensure diversity in genomic sequencing, build trust and partnerships, and advocate for equitable access to emerging therapies. An early attempt to address the lack of diversity in genomic databases was the Human Genome Diversity Project, through which human genomes from around the globe were sequenced in order to better understand genomic diversity.33 A further step is the NIH’s All of Us research project, a national effort to enhance diversity in genome sequencing in part through partnerships with numerous hospital systems and community health advocacy groups such as the Black Women’s Health Imperative.34 This work and that of other organizations has promise as a step toward making clinical applications of gene editing more equitable across all populations, but further work is necessary.
Increasing diversity of genomic databases is necessary not only to produce more relevant research and clinical applications, but also to create a sense of inclusion and trust among historically disenfranchised minority communities. Establishing such partnerships in somatic gene therapy research and its clinical applications must happen on a health systems level, not just on a patient-clinician level. The duty of balancing risks and ensuring informed consent cannot solely be fulfilled by adhering to the normal human subjects protections procedures provided by institutional review boards.16 Medical and research communities need to prove to the public that inclusion of minority groups in genetic research and equal access to the benefits of this research are high priorities and that opinions and concerns of minority communities are considered when designing protocols and developing new therapies.14 Input from stakeholder groups—both experts and laypeople—tasked specifically with considering long-term implications of somatic gene therapy for minority groups is crucial. These stakeholder groups should be assembled from communities that will face the direct risks and potential benefits of research. If a gene editing study for sickle cell disease (SCD) is conducted, for example, input should be sought from patients with SCD and from advocacy groups like the Sickle Cell Disease Association of America to promote equitable access to somatic gene therapy upon its arrival in the clinic.
Partnerships with minority communities must involve transparency, education of the public about gene editing and research studies design, and meticulous informed consent.6,35 The National Human Genome Research Institute has several groups dedicated to exploring health disparities in genomics along with avenues of engaging minority groups and the public.36-38 These initiatives should be expanded and serve as models for larger-scale efforts to engage minority groups and build trust. Transparency will require translating published materials of relevant studies into language interpretable by the public and making discussions of the ethics and science related to applications of gene editing available outside academic medical centers and scientific journals. The scientific community should devote resources not only to engage and educate the public but also to study the effectiveness of these interventions. The same methodological rigor that is applied to the science of gene editing must be applied to public education and dissemination of research results.
Conversations about the ethics of clinical applications of gene editing and its potential impacts on minorities have been happening for years.9,11,39 These conversations should continue to move into the public sphere. NIH funding is now available to study the ethics of genomics and its applications; the issues of access and justice need urgent exploration.40 It will be important to reach out to minority communities directly to ascertain their specific concerns. One such study, examining perspectives of SCD patients on gene editing in SCD, is already underway.41
To ensure just distribution of risks and benefits of research, the medical-scientific community must foster trust and open communication with historically disenfranchised groups. Basic scientists, physicians, and health policymakers must work to ensure justice in gene therapy locally and worldwide. While gene editing poses a risk of maintaining or even widening health inequities, it could also be a tool to reduce them. One main goal of CRISPR/Cas9 somatic gene therapy can and should be its use as a form of preventive medicine to address specific racial and ethnic disparities in health outcomes. Toward this end, researchers and clinicians must continue to act as educators, builders of community partnerships, and advocates for just and equitable access to these new technologies.
- Jasin M. Scientific Background on Gene Editing Technologies. New York, NY: Vimeo; 2015. https://vimeo.com/149184042. Accessed April 27, 2016.
Doudna J, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. doi:10.1126/science.1258096.
- Mali P, Esvelt KM, Church GM. Cas9 as a versatile tool for engineering biology. Nat Methods. 2013;10(10):957-963.
CAR T cells more powerful when built with CRISPR, MSK researchers find [press release]. New York, NY: Memorial Sloan Kettering Cancer Center; February 22, 2017. https://www.mskcc.org/press-releases/car-cells-more-powerful-when-built-crispr-msk-researchers-find. Accessed August 22, 2017.
Clinicaltrials.gov. Search term: CRISPR. https://clinicaltrials.gov/ct2/results?cond=&term=crispr&cntry1=&state1=&SearchAll=Search+all+studies&recrs. Accessed August 18, 2017.
- Wirth T, Parker N, Ylä-Herttuala S. History of gene therapy. Gene. 2013;525(2):162-169.
- Cai L, Bai H, Mahairaki V, et al. A universal approach to correct various HBB gene mutations in human stem cells for gene therapy of beta-thalassemia and sickle cell disease. Stem Cells Transl Med. 2018;7(1):87-97.
Buchanan A, Brock D, Daniels N, Wikler D. Positive and negative genetic interventions. In: From Chance to Choice: Genetics and Justice. Cambridge, UK: Cambridge University Press; 2007:107-154.
National Academies of Sciences, Engineering, and Medicine. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: National Academies Press; 2017.
De Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics; European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE [published online ahead of print January 12, 2018]. Eur J Hum Genet. doi:10.1038/s41431-017-0076-0.
On human gene editing: international summit statement [press release]. Washington, DC: National Academies of Sciences, Engineering, Medicine; December 3, 2015. http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a. Accessed March 29, 2018.
- Ormond KE, Mortlock DP, Scholes DT, et al. Human germline genome editing. Am J Hum Genet. 2017;101(2):167-176.
- ACMG Board of Directors. Genome editing in clinical genetics: points to consider—a statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(7):723-724.
- Corbie-Smith G, Thomas SB, Williams MV, Moody-Ayers S. Attitudes and beliefs of African Americans toward participation in medical research. J Gen Intern Med. 1999;14(9):537-546.
Grady D. White doctors, black subjects: abuse disguised as research. New York Times. January 23, 2017. http://www.nytimes.com/2007/01/23/health/23book.html?mcubz=0. Accessed March 29, 2018.
- Shivayogi P. Vulnerable population and methods for their safeguard. Perspect Clin Res. 2013;4(1):53-57.
- Gee GC, Ford CL. Structural racism and health inequities: old issues, new directions. Du Bois Rev. 2011;8(1):115-132.
Bulger RE, Bobby EM, Fineberg HV, eds; Institute of Medicine Committee on the Social and Ethical Impacts of Developments in Biomedicine. The social context of bioethical problem solving. In: Society’s Choices: Social and Ethical Decision Making in Biomedicine. Washington, DC: National Academy Press; 1995:43-53.
Hunt KA, Gaba A, Lavizzo-Mourey R. Racial and ethnic disparities and perceptions of health care: does health plan type matter? Health Serv Res. 2005;40(2):551-576.
- Benz J, Espinosa O, Welsh V, Fontes A. Awareness of racial and ethnic health disparities has improved only modestly over a decade. Health Aff (Milwood). 2011;30(10):1860-1867.
Rainie L, Hefferon M, Sciupac EP, Anderson M. American voices on ways human enhancement could change our future. Pew Research Center. http://www.pewinternet.org/2016/07/26/american-voices-on-ways-human-enhancement-could-shape-our-future/. Published July 26, 2016. Accessed August 17, 2017.
- Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291(5507):1304-1351.
Genomics England website. https://www.genomicsengland.co.uk/about-genomics-england/how-we-work/. Accessed April 27, 2018.
- Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161-164.
National Human Genome Research Institute; European Bioinformatics Institute. GWAS catalog. https://www.ebi.ac.uk/gwas/. Accessed January 17, 2018.
- Lessard S, Francioli L, Alfoldi J, et al. Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci. Proc Natl Acad Sci USA. 2017;114(52):e11257-e11266.
United States Census Bureau. Wealth, asset ownership, and debt of households detailed tables: 2013. https://www.census.gov/data/tables/2013/demo/wealth/wealth-asset-ownership.html. Updated May 4, 2017. Accessed January 17, 2018.
- Williams DR, Priest N, Anderson NB. Understanding associations between race, socioeconomic status and health: patterns and prospects. Health Psychol. 2016;35(4):407-411.
National Center for Health Statistics. Health, United States, 2015: With Special Feature on Racial and Ethnic Health Disparities. Hyattsville, MD: National Center for Health Statistics; 2016. https://www.cdc.gov/nchs/data/hus/hus15.pdf. Accessed August 17, 2017.
- Williams DR. Miles to go before we sleep: racial inequities in health. J Health Soc Behav. 2012;53(3):279-295.
- Wang J, Zuckerman IH, Miller NA, Shaya FT, Noel JM, Mullins CD. Utilizing new prescription drugs: disparities among non-Hispanic whites, non-Hispanic blacks, and Hispanic whites. Health Serv Res. 2007;42(4):1499-1519.
- Hardeman RR, Medina EM, Kozhimannil KB. Structural racism and supporting black lives—the role of health professionals. N Engl J Med. 2016;375(22):2113-2115.
Stanford University. Human Genome Diversity Project. http://www.hagsc.org/hgdp/. Accessed November 5, 2017.
National Institutes of Health. All of Us Research Program website. https://allofus.nih.gov. Accessed November 5, 2017.
- Marron JM, Joffe S. Ethical considerations in genomic testing for hematologic disorders. Blood. 2017;130(4):460-465.
National Human Genome Research Institute. Community outreach and public education. https://www.genome.gov/10001279/community-outreach-education/. Published December 12, 2016. Accessed August 18, 2017.
National Human Genome Research Institute. Education and community involvement branch. https://www.genome.gov/11008538/education-and-community-involvement-branch/. Published December 1, 2016. Accessed August 17, 2017.
National Human Genome Research Institute. Initiatives and resources for minority and special populations. https://www.genome.gov/10001192/initiatives-and-resources-for-minority-and-special-populations/. Published February 3, 2017. Accessed August 17, 2017.
Personal Genetics Education Project. Industry forum for forging community partnerships. https://pged.org/industry-forum. Accessed July 30 2017.
National Institutes of Health. Ethical, legal, and social implications (ELSI) of genomics exploratory/developmental research grant program (R21). https://grants.nih.gov/grants/guide/pa-files/PA-17-323.html. Published August 3, 2017. Accessed August 18, 2017.
National Institutes of Health Clinical Center. Examining the knowledge, attitudes, and beliefs of sickle cell disease patients, parents of patients with sickle cell disease, and providers towards the integration of CRISPR in clinical care. https://clinicaltrials.gov/ct2/show/NCT03167450?term=crispr&rank=3. Published June 15, 2017. Accessed August 15, 2017.