Development and Applications of CRISPR-Cas9 for Genome Engineering
Open accessAbstract
Recent advances in genome engineering technologies based on the CRISPR-associated RNA-guided endonuclease Cas9 are enabling the systematic interrogation of mammalian genome function. Analogous to the search function in modern word processors, Cas9 can be guided to specific locations within complex genomes by a short RNA search string. Using this system, DNA sequences within the endogenous genome and their functional outputs are now easily edited or modulated in virtually any organism of choice. Cas9-mediated genetic perturbation is simple and scalable, empowering researchers to elucidate the functional organization of the genome at the systems level and establish causal linkages between genetic variations and biological phenotypes. In this Review, we describe the development and applications of Cas9 for a variety of research or translational applications while highlighting challenges as well as future directions. Derived from a remarkable microbial defense system, Cas9 is driving innovative applications from basic biology to biotechnology and medicine.
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The paper notes that adapting bacterial CRISPR systems for RNA-guided cleavage of complementary DNA transformed mammalian gene editing.
“Repurposing bacterial “CRISPR” systems to facilitate RNA-guided cleavage of complementary DNA has revolutionized the field of gene editing in mammalian cells 1–4.”
From A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells (2018) · cites this paper as [4]
The DNA-targeting Cas9 nuclease is typically encoded within 3000 to 4800 base pairs and is found in close genomic proximity to its cognate CRISPR array.
“The DNA-targeting Cas9 nuclease is typically encoded within 3000 to 4800 base pairs (bp) of coding sequence and found in close genomic proximity to its cognate CRISPR array (60).”
From Sequence modeling and design from molecular to genome scale with Evo (2024) · cites this paper as [60]
CRISPR technology provides a precise, efficient, and versatile tool for targeted DNA modification in various organisms.
“The development of CRISPR technology has revolutionized genome editing by providing a precise, efficient, and versatile tool for targeted DNA modification in various organisms5,6.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [5]
A smaller Cas9 gene could be used, but this has additional implications on efficacy.
“A smaller Cas9 gene could be used, but this has additional implications on efficacy.1”
From What is CRISPR/Cas9? (2016) · cites this paper as [1]
The CRISPR/Cas9 system is a more flexible and cost-effective genome-editing method based on RNA-guided endonuclease activity than TALENs.
“As an alternative, the CRISPR/Cas9 system is a more flexible and cost-effective method for genome editing based on RNA-guided endonuclease activity 20 .”
From TALEN and CRISPR/Cas9-mediated genome editing in the early-branching metazoan Nematostella vectensis (2014) · cites this paper as [20]
The Cas9 nuclease is directed by a single-guide RNA to modify a specific chromosomal DNA sequence by inducing a sequence-specific double-strand break.
“The Cas9 nuclease is directed by a single-guide RNA (sgRNA) to modify a specific chromosomal DNA sequence by inducing a sequence-specific double-strand break (DSB) (3, 4).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [3]
Off-target cleavage is a major concern for any nuclease therapy, but studies show off-target effects are not a substantial impediment to human genome-engineering applications and do not appear to be an obstacle for applications targeting nonhuman genomes.
“Together with recent improvements on CRISPR target specificity with dual-guide RNA designs (33)(34)(35), these studies show that off-target effects are not a substantial impediment to human genome-engineering applications and certainly do not appear to be an obstacle for applications that target nonhuman genomes (36).”
From RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection (2014) · cites this paper as [36]
The concentration of Cas9 nuclease enzyme and the length of time Cas9 is expressed are both important when limiting off-target activity.
“The concentration of the Cas9 nuclease enzyme and the length of time Cas9 is expressed are both important when limiting off-target activity. 1”
From What is CRISPR/Cas9? (2016) · cites this paper as [1]
AAV has previously been a favoured option for gene delivery.
“AAV has previously been a favoured option for gene delivery.1”
From What is CRISPR/Cas9? (2016) · cites this paper as [1]
AAV delivery system may be too small to allow efficient transduction of the Cas9 gene.
“However, this delivery system may be too small to allow efficient transduction of the Cas9 gene. 1”
From What is CRISPR/Cas9? (2016) · cites this paper as [1]
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- Authors
- Hsu, P. D., Lander, E. S., & Zhang, F.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Zhang, Feng
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 6
- Pages
- 1262-1278
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4343198
- OpenAlex
- W2096261947
- Semantic Scholar
- db50244db3297a343b9ea120db842f0329169b26
- Cited by
- 5,762
- References
- 101
- Citations by year
- 2026: 261 · 2025: 369 · 2024: 410 · 2023: 416 · 2022: 483 · 2021: 529 · 2020: 571 · 2019: 556 · 2018: 574 · 2017: 504 · 2016: 539 · 2015: 441 · 2014: 100 · 2013: 2
- FWCI
- 48.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- PMC
- Funders
- National Institutes of Health
- National Institute of Mental Health (DP1MH100706)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097768)
- National Institute of Neurological Disorders and Stroke (R01NS073124)
- National Center for Chronic Disease Prevention and Health Promotion (DP1‑MH100706)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- CRISPR/Cas9, genome editing, RNA-guided endonuclease, gene function, gene perturbation, genome organization, biotechnology applications, therapeutic applications
- MeSH terms
- Animals, Bacteria, Eukaryotic Cells, Genetic Engineering, Humans, Streptococcus pyogenes, Genome, Gene Targeting, CRISPR-Cas Systems
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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