By Angel Feliz
From the characterization of the double-helix structure of DNA, to the development of the first chimeric recombinant DNA in 1972, to the mapping of the human genome in 2001, technological improvements have historically led to advances in conceptual understanding of molecular and cellular biology. These conceptual advances in turn inform the next generation of technology.
Perhaps one of the most groundbreaking technologies to emerge from the mid-2000s were precise genome editing tools such as the bacteria-derived CRISPR/Cas9 system. Genome editing using CRISPR/Cas9 unlocked the potential for personalized therapy for human genetic diseases and infectious diseases. Recently, CRISPR has gained much attention due to the 2023 approval of a novel cell-based gene therapy for sickle cell patients by the US Food and Drug Administration (FDA). This approval provides hope for the many patients and families struggling with the limitations of the disease itself as well as limitations in current treatment options. Novel therapeutic approaches emerging from the genome-editing revolution have the potential to cure devastating inherited disorders while addressing diseases traditionally neglected by the pharmaceutical industry.
In the context of the American healthcare system, often riddled with systemic biases, how can we ensure that advances in biomedical tools remain accessible to underserved and historically marginalized patients? In an era where emerging biotechnologies are optimized at an ever-increasing pace, where do we as scientists find balance between scientific innovation and ensuring equitable health outcomes? As a community of scientists pursuing research for the benefit of humanity, it is important to examine personal, interpersonal, and institutional biases in the sciences and medicine to ensure an equitable and healthy future for all.
In this piece, I explore the future of genome editing technology like CRISPR/Cas9 through recent advancements in application, ethical considerations, relevant challenges, and future directions of the technology within the coming years.
Curing Sickle Cell Anemia
According to the Center for Disease Control and Prevention (CDC), approximately 100,000 Americans are affected by sickle cell disease1. Among the populace, African Americans have a proportionally higher incidence of sickle cell disease with an estimated 1 in 13 Black or African American child being born with the blood disorder. Sickle cell disease is a group of inherited blood disorders characterized by a mutation in hemoglobin, a protein found in red blood cells, that alters the beta-globin fibers that provide structural support to red blood cells. The sickle-shaped red blood cells result in limited oxygen delivery and constricted blood flow that overtime can cause chronic pain and organ damage in what are known as vaso-occlusive crises (VOCs)2.
Sickle cells live about 10 to 20 days while healthy red blood cells live for about 120 days before needing to be replaced, and it is this deficit that results in anemia for patients3. Sickle cell patients additionally suffer from vision problems, increased infection rates, and periodic episodes of pain in the chest, abdomen, and joints. Traditional approaches to treat sickle cell disease involve a bone marrow transplant. However, about 80% of sickle cell patients are unable to find a compatible donor in the United States4.
Much excitement exists in the biomedical field due to the development of personalized cell-based gene therapies like the CRISPR/Cas9 gene-editing system that would circumvent the donor crisis. This new technology shows potential in effectively treating inherited genetic disorders such as Duchene muscular dystrophy (DMD) and, most recently, sickle cell anemia5.
On December 8, 2023, the FDA announced the approval of two milestone treatments, Casgevy and Lyfgenia, for patients with sickle cell disease who are twelve years or older and present recurring VOCs within the last two years6. While Lyfgenia utilizes a lentiviral vector to deliver genetic modifications to the patients’ blood stem cells, Casgevy is the first FDA-approved treatment to use CRISPR/Cas9. In both cases, the patients’ own blood stem cells are collected, modified ex vivo, then transplanted in a one-time single-dose fashion. The primary outcome from phase trials show that patients treated with Casgevy were free of VOC episodes for at least 12 consecutive months during the 24-month follow-up period. Of the 31 patients who received adequate follow-up, 29 were free of VOCs for at least a year, resulting in a 93.5% success rate7. Furthermore, none demonstrated signs of transplant rejection. It is remarkable to see technology that has only been around for about a decade make significant improvements for both physicians dedicated to curing inherited genetic disorders and patients with few therapeutic options. When viewed against the backdrop of the American healthcare system, these successes raise new challenges and questions about equitable access.
Bridging The Gap
To achieve fair and equitable health outcomes for all, it is necessary to recognize and address the underlying social determinants of health among individuals across diverse communities. Such disparities in health outcomes or access to healthcare services are often caused by social, economic, and environmental factors.
According to the Pew Research Center, 63% of Black adults surveyed cite lack of access to quality healthcare as the major reason why Black Americans face worse health outcomes8. Research shows that Black communities tend to have fewer primary care physicians, trauma centers, and pharmacies9. Limited access to primary care providers and healthcare facilities in predominantly African American communities can hinder timely and preventive care. This lack of access continues to exacerbate health conditions and increases long-term healthcare costs.
A report from KFF of coverage rates by race and ethnicity in 2022 determined that African Americans are more likely to be uninsured (10%) than their White counterparts (6.6%), which can result in delayed or foregone medical care thus leading to poorer health outcomes10. Even with health insurance, out-of-pocket costs such as deductibles, copayments, and premiums can pose financial barriers. The COVID-19 pandemic further exacerbated disparities between Black and other racial minorities compared to White Americans. In fact, data from the U.S. Census Bureau reveals a widening gap between the average life expectancy for Black and other racial minorities compared to White Americans11.
For these new novel CRISPR-based treatments to be applied equitably, the cost per treatment must be made affordable to the patient. In an interview with 15-year-old Johnny Lubin, among the first ever treated for sickle cell anemia with CRISPR, CNN medical correspondent Meg Tirrell shared that this procedure could be very expensive with an estimated $2,000,000 dollars per treatment12. Cost of treatment remains a burdensome challenge overall to marginalized and low-income communities and is one among many determinants driving health inequity. While these social determinants of health remain largely unaddressed, equitable healthcare in the context of genome-editing therapeutic novelties will be a struggle.
CRISPR Twenty Years From Now
Looking ahead two decades from now, the trajectory of CRISPR technology promises ground-breaking advances and a broader range of applications beyond medicine. With so many advances in emerging technologies, what should we expect from CRISPR in the coming years? What kinds of diseases will be targeted with this technology?
According to Dr. Jennifer Doudna, co-founder of CRISPR, the answer lies in the gut13. More specifically, in the immense population of tiny microorganisms living in and on our bodies. During a TED talk event held this previous September, Dr. Doudna said that researchers can now use CRISPR “in a way that will allow us to go to the next level by editing genes beyond the individual organism.” CRISPR provides us with the ability “to edit entire populations of entire microbes” like never before14.
Unlike antibiotics, which affect the entire microbiome, new CRISPR technology allows for the targeting of specific genes within a microbe population. Termed ”precision microbiome editing” by Dr. Doudna, this approach will allow scientists to uncover new insights into disease pathologies.
As technology advances, it becomes increasingly important to establish clear ethical guidelines that govern its applications. The issue of ‘designer babies’ and the fears that underpin the misuse of this technology is currently a hot topic in society. Consider the case of Chinese biophysicist Dr. He Jiankui, who created the first gene-edited children in an attempt to make them resistant to HIV. Chinese authorities sentenced Dr. He on December 30, 2019 to three years in prison for “illegal medical practices” in addition to being charged a ¥3,000,000 yuan fine (equivalent to about $420,000). This case demonstrates how striking a balance between scientific progress and ethical responsibility will be critical in addressing concerns about unintended consequences, potential misuse, and the societal impact of genome editing.
While the future of CRISPR holds great promise, it requires a cautious approach moving forward. Scientists must maintain ethical standards, overcome technical challenges, navigate legal complexities, and investigate novel applications concurrently as CRISPR usage continues to evolve.
1. Centers for Disease Control and Preven- tion. (2023, July 6). Data & statistics on Sick- le Cell Disease. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbd- dd/sicklecell/data.html
2. Sickle Cell Anemia News. (2022, July 18). Vaso-occlusive crisis. Sickle Cell Disease News. https://sicklecellanemianews.com/ vaso-occlusive-crisis/
3. Mayo Foundation for Medical Educa- tion and Research. (2023, December 22). Sickle cell anemia. Mayo Clinic. https:// www.mayoclinic.org/diseases-conditions/ sickle-cell-anemia/symptoms-causes/syc- 20355876
4. CNN Health. (2023, December 8). FDA ap- proves two gene therapies for sickle cell, bringing hope to thousands with the disease. https://www.cnn.com/2023/12/08/health/ first-crispr-gene-editing-treatment-sickle- cell-disease-scn/index.html
5. Wang, Y., Huang, C., & Zhao, W. (2022). Re- cent advances of the biological and biomed- ical applications of CRISPR/Cas systems. Molecular Biology Reports, 49(7), 7087-7100. FDA. (2023, December 8). FDA approves first gene therapies to treat patients with sickle cell disease. U.S. Food and Drug Adminis- tration. https://www.fda.gov/news-events/ press-announcements/fda-approves-first- gene-therapies-treat-patients-sickle-cell- disease
6. U.S. National Library of Medicine. (2023, December 11). A safety and efficacy study evaluating CTX001 in subjects with severe sickle cell disease – full text view. Clinical- Trials.gov. https://classic.clinicaltrials.gov/ ct2/show/NCT03745287
7. Pew Research Center. (2023, December 21). 5 facts about Black Americans and health care. Pew Research Center. https://www.pe- wresearch.org/short-reads/2023/12/21/5- facts-about-black-americans-and-health- care/
8. Gaskin, D. J., Dinwiddie, G. Y., Chan, K. S., & McCleary, R. R. (2012). Residential segre- gation and the availability of primary care physicians. Health services research, 47(6), 2353-2376.
9. Latoya Hill, S. A. (2024, January 11). Health coverage by Race and ethnicity, 2010- 2022. KFF. https://www.kff.org/racial-equi- ty-and-health-policy/issue-brief/health-cov- erage-by-race-and-ethnicity/
10. Nambi Ndugga and Samantha Artiga. (2023, April 21). Disparities in health and health care: 5 key questions and answers. KFF. https://www.kff.org/racial-equi- ty-and-health-policy/issue-brief/disparities- in-health-and-health-care-5-key-question- and-answers/
11. CNN. (2023, December 8). Teen is one of the first ever to get his genes edited. why he says the process is “cool and freaky.” YouTube. https://www.youtube.com/ watch?v=0xv0CBujwZU
12. Kahn, J. (2023, September 19). CRISPR pioneer Jennifer Doudna has the guts to take on the microbiome. Wired. https://www. wired.com/story/crispr-jennifer-doudna-mi- crobiome/
13. TED. (2023b, September 27). CRISPR’s next advance is bigger than you think | Jen- nifer Doudna | Ted. YouTube. https://www. youtube.com/watch?v=HANo__Z8K6s
14. Normile, D. (2019, December 30). Chinese scientist who produced genetically altered babies sentenced to 3 years in jail. Science. org. https://www.science.org/content/arti- cle/chinese-scientist-who-produced-genet- ically-altered-babies-sentenced-3-years-jail