The field of human genome editing has exploded in the past 10 years, thanks to the revolutionary gene editing technology known as CRISPR. In 2012, Jennifer Doudna and Emmanuelle Charpentier elucidated the mechanism of the CRISPR-Cas9 system, an ancient defense system evolved in bacteria to detect and cut the DNA of invading viruses, and showed that it could be leveraged for targeted genome editing in vitro.[i] Feng Zhang and his team at the Broad Institute subsequently showed that CRISPR-Cas9 could successfully modify target genes in mammalian cells.[ii] These two discoveries led to the implementation of CRISPR in many facets of basic research, the formation of new biotechnology companies dedicated to using CRISPR for a variety of purposes,[iii] and the successful use of CRISPR gene therapies in patients with genetic diseases. In recognition of CRISPR’s extraordinary potential, the Royal Swedish Academy of Sciences – which normally bestows Nobel Prizes several decades after a scientific discovery – awarded the 2020 Nobel Prize in Chemistry to Doudna and Charpentier, a mere eight years after their seminal paper, for discovering the genetic tools that “have taken the life sciences into a new epoch.”[iv]
When used for human genome editing, the CRISPR system only consists of three components: a Cas (CRISPR-associated) enzyme, which is likened to “molecular scissors,” a “guide RNA,” a piece of RNA complementary to the target DNA sequence, and a repair template, the desired sequence of DNA. The guide RNA binds to the desired stretch of DNA, allowed Cas to make a double-stranded break in the DNA. The repair template then becomes incorporated into the cell’s genome as it repairs the break. [v]
This basic approach has already been used to effectively treat several genetic conditions. Over the course of the past two years, patients with sickle cell disease and beta thalassemia, monogenic diseases characterized by defective hemoglobin, had stem cells from their bone marrow removed and edited with CRISPR so that they would begin expressing fetal hemoglobin (which normally is turned off shortly after birth), after which they received infusions of these cells.[vi] More than a year after treatment, the patients presented high levels of blood hemoglobin and a drastic reduction in painful symptoms.[vii] Trials are currently underway to treat genetic forms of blindness in vivo by injecting a harmless virus containing the CRISPR machinery into the back of the eye.[viii] A June 2021 study in which researchers eliminated the production of a defective liver protein that can cause fatal side effects showed that CRISPR can be safe and effective when injected directly into the bloodstream, likely an important step for the future of CRISPR therapeutics.[ix]
Congenital diseases represent a significant portion of health conditions faced globally, and many cause serious pain, disability, morbidity, or early mortality. The development of CRISPR technology has resulted in rapid increases in funding, research, and potential ability to treat such diseases via human genome editing. Results so far are promising, and it is likely that further research will improve the accessibility of this technology.
1 Jinek, M., et al. “A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity.” Science, vol. 337, no. 6096, 2012, pp. 816–821., doi:10.1126/science.1225829.
2 Ran, F. A., et al. “Genome Engineering Using the Crispr-cas9 System.” Nature Protocols, vol. 8, no. 11, 2013, pp. 2281–2308., doi:10.1038/nprot.2013.143.
2 Shaffer, C. “CRISPR Startups Give Genome Editing Several New Twists.” Genetic Engineering & Biotechnology News, 4 Aug. 2020, www.genengnews.com/insights/crispr-startups-give-genome-editing-several-new-twists/.
5 Pak, E. “CRISPR: A Game-Changing Genetic Engineering Technique.” Science in the News, The Graduate School of Arts and Sciences at Harvard University, 31 July 2014, sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/.
6 Stein, R. “1st Patients to Get CRISPR Gene-Editing Treatment Continue to Thrive.” NPR, 15 Dec. 2020, www.npr.org/sections/health-shots/2020/12/15/944184405/1st-patients-to-get-crispr-gene-editing-treatment-continue-to-thrive.
7 Frangoul, H., et al. “CRISPR-Cas9 Gene Editing for Sickle Cell Disease AND Β-THALASSEMIA.” New England Journal of Medicine, vol. 384, no. 3, 2021, pp. 252–260., doi:10.1056/nejmoa2031054.
8 Stein, R. “In a 1st, Scientists Use Revolutionary Gene-Editing Tool to Edit Inside a Patient.” NPR, NPR, 4 Mar. 2020, www.npr.org/sections/health-shots/2020/03/04/811461486/in-a-1st-scientists-use-revolutionary-gene-editing-tool-to-edit-inside-a-patient.