CRISPR-Cas9: Timeline of key events

CRISPR-Cas9: Timeline of key events

• In December 1987, researchers Amemura, Ishino, Makino, Nakata, Shinagawa, Takase, and Wachi at Osaka University first published findings on the CRISPR mechanism, marking the foundational discovery in gene editing using CRISPR-Cas9.

• On 18 January 2000, scientists Mojica, Diez-Villasenor, Soria, and Juez at the University of Alicante and University Miguel Hernandez identified more clustered DNA repeats in bacteria and archaea, naming them Short Regularly Spaced Repeats (SRSR), a critical advancement in understanding CRISPR’s prevalence.

• In March 2002, Mojica, Jansen, Embden, Gaastra, and Schouls at Utrecht University coined the term “CRISPR-Cas9” for the first time in scientific literature, formally introducing the nomenclature now standard in genetic engineering.

• In 2005, Jennifer Doudna and Jillian Banfield at the University of California, Berkeley began investigating CRISPR systems, laying the groundwork for later breakthroughs in CRISPR-Cas9 as a gene-editing tool.

• On 1 August 2005, French researchers Bolotin, Quinquis, Sorokin, and Ehrlich at the Institut National de la Recherche Agronomique proposed that CRISPR spacer sequences can provide acquired immunity in bacterial cells by degrading viral DNA, suggesting a defense function for CRISPR systems.

• On 11 November 2005, American scientists Haft, Selengut, Mongodin, and Nelson from The Institute for Genomic Research identified new families of Cas genes, enhancing the understanding of how CRISPR systems protect bacteria from viral invasion.

• On 23 March 2007, experiments by Barrangou, Horvath, Fremaux, and Deveau at Danisco USA Inc demonstrated for the first time that CRISPR sequences, along with Cas9 genes, confer adaptive immunity in bacteria against phages, providing direct experimental evidence of CRISPR’s functional mechanism.

• In 2008, researchers demonstrated that DNA, not RNA, is the primary molecular target of most CRISPR-Cas systems, clarifying the mechanism of action in gene editing.

• In February 2008, scientists introduced the term “protospacer” to describe the viral DNA sequence that matches a spacer sequence in the CRISPR array, establishing a key concept in the CRISPR-Cas9 mechanism.

• In August 2008, scientists at Wageningen University, University of Sheffield, and the National Institutes of Health characterized the RNA processing pathway in the CRISPR system, providing insights into how CRISPR RNA guides the Cas proteins.

• In December 2008, researchers Carte, Wang, Li, and Terns at the University of Georgia and Florida State University published the gene silencing pathway involving RNA in CRISPR-Cas mechanisms, revealing a crucial step in the immune defense process.

• In 2011, a formal classification system for the CRISPR-Cas systems was proposed, facilitating standardized categorization and comparative studies of the diverse CRISPR systems.

• In March 2011, Emmanuelle Charpentier and Jennifer Doudna, along with Hinek and Hauser at the University of California Berkeley and Umeå University, began collaborative research to investigate the Cas9 enzyme, setting the stage for major breakthroughs in gene editing.

• In April 2012, Dupont initiated the first commercial use of CRISPR-Cas9 technology, marking a shift from academic to industrial application.

• In May 2012, the first patent application for CRISPR-Cas9 technology was submitted by Doudna and Charpentier, representing University of California Berkeley and University of Vienna, initiating a wave of intellectual property activity in the field.

• On 17 August 2012, Jinek, Chylinski, Fonfara, Hauer, Doudna, and Charpentier at the University of California Berkeley published a paper describing a novel gene-editing method using CRISPR-Cas9, demonstrating programmable, site-specific genome modification.

• On 25 September 2012, researchers at Vilnius University, including Siksnys, Gasiunas, Barrangou, and Horvath, published findings showing the potential of CRISPR-Cas9 to precisely edit DNA, contributing parallel advancements to the field.

• On 12 December 2012, Feng Zhang at the Broad Institute and Massachusetts Institute of Technology submitted a fast-track application to the US patent office for CRISPR-Cas9 technology, intensifying the patent race over its ownership.

• In January 2013, CRISPR-Cas9 was successfully used for genome editing in human cells, representing the first application of the technology in human genomic research.

• In January 2013, CRISPR-Cas9 was also used to edit the genome of zebrafish, showcasing its applicability in animal models for developmental and genetic research.

• In February 2013, Bikard and Murrafini at Rockefeller University demonstrated that CRISPR-Cas9 could be programmed to repress or activate gene transcription, extending its application beyond editing to gene regulation.

• In March 2013, CRISPR-Cas9 was used to edit the genome of Saccharomyces cerevisiae, a yeast species crucial to food and beverage industries, highlighting its versatility in industrial biotechnology.

• On 1 April 2013, Sampson and Weiss at Emory University demonstrated that CRISPR-Cas9 mediated regulation could control the expression of endogenous bacterial genes, revealing its role in bacterial gene regulatory networks.

• In August 2013, CRISPR-Cas9 was used to successfully engineer the genome of a rat, broadening its application to mammalian genetic models and biomedical research.

• In August 2013, CRISPR-Cas9 was successfully used to engineer the genomes of various plant species including rice, wheat, Arabidopsis, tobacco, and sorghum, demonstrating its utility in agricultural biotechnology.

• In August 2013, significant improvements were made to the specificity of the CRISPR-Cas system, reducing off-target effects and enhancing the accuracy of gene editing.

• In March 2015, Feng, Dai, Mou, Cooper, Shi, and Cai from Shenzhen University, the University of Pittsburgh Medical Center, and Guangxi University proposed using CRISPR-Cas9 with stem cells to generate human organs in transgenic pigs, opening new avenues for xenotransplantation.

• On 26 March 2015, US scientists Lamphier and Urnov publicly called for a voluntary worldwide moratorium on the use of genome editing tools, including CRISPR-Cas9 and zinc fingers, to modify human reproductive cells due to ethical concerns.

• On 15 April 2015, the National Institutes of Health (NIH) declared it would not provide funding for any genome editing research involving human embryos, establishing a clear policy on the ethical boundaries of federal research funding.

• On 22 April 2015, the UK’s Nuffield Council on Bioethics launched a working group to examine the legal, institutional, and international policy dimensions of genome editing, signaling growing global interest in ethical governance.

• On 1 May 2015, researchers Huang, Liang, Xu, and Zhang at Sun Yat-sen University published the first report of genes edited in human embryos, sparking international ethical and scientific debates about the appropriate use of CRISPR-Cas9.

• On 2 September 2015, the UK’s Medical Research Council (MRC) and other leading research organizations expressed support for using genome editing tools like CRISPR-Cas9 in preclinical research, underlining its scientific potential within ethical boundaries.

• On 11 September 2015, the Hinxton Group issued a statement noting that many ethical and moral questions posed by CRISPR and gene editing had historical precedents, emphasizing the need for responsible, informed discussions rather than reactionary bans.

• On 15 September 2015, the UK Nuffield Council on Bioethics held its first workshop to define ethical concerns related to emerging genome editing technologies, focusing on implications for future policy development.

• On 18 September 2015, UK scientist Kathy Niakan at the Crick Institute formally sought a license to genetically modify human embryos to study early developmental gene functions, marking a regulatory milestone in genome research.

• On 25 September 2015, researchers Zhang, Zetsche, Gootenberg, Abudayyeh, and Slaymaker at the Broad Institute and MIT discovered the Cpf1 protein, which simplified CRISPR-based gene editing by enabling alternative DNA targeting mechanisms.

• On 5 October 2015, George Church at Harvard University used CRISPR-Cas9 to modify 60 genes in pig embryos in an effort to develop organs suitable for human transplantation, advancing transgenic animal research.

• On 6 October 2015, UNESCO’s International Bioethics Committee called for a ban on the genetic editing of the human germline, emphasizing the global ethical risks associated with heritable gene modifications.

• On 16 November 2015, US scientists DiCarlo, Chavez, Dietz, Esvelt, and Church from Harvard University and Swiss Federal Institute of Technology in Zurich published a technique to overwrite changes made by CRISPR-Cas9, introducing methods for correcting or reversing gene edits.

• On 23 November 2015, researchers Gantz, Jasinskiene, Tatarenkova, Fazekas, Macias, Bier, and James at University of California San Diego and University of California Irvine genetically modified mosquitoes using CRISPR-Cas9 to prevent them from carrying the malaria parasite, showing potential for disease control.

• On 1 December 2015, the International Summit on Human Gene Editing convened in Baltimore, involving leaders like Doudna, Church, and Zhang, to discuss scientific, medical, ethical, and governance issues related to recent advances in human gene editing.

• On 31 December 2015, CRISPR was successfully used to improve muscle function in a mouse model of Duchenne muscular dystrophy by Nelson, Gersbach, Hakim, Ousterout, and Thakore from Duke University, University of Missouri, University of North Carolina, MIT, and Harvard University, highlighting therapeutic applications.

• On 6 January 2016, Kleinstiver, Pattanayak, Prew, Tsai, Nguyen, Zheng, and Joung at Harvard University published an improved version of CRISPR-Cas9 with reduced risk of off-target DNA breaks, enhancing editing precision and safety.

• On 1 February 2016, UK scientist Niakan at the Crick Institute was authorized to genetically modify human embryos using CRISPR-Cas9, marking a regulatory milestone for embryo research in the UK.

• On 16 May 2016, Komor, Kim, Packer, Zuris, and Liu at Harvard University published a new base editing technique allowing genome alterations without double-strand DNA cleavage or donor DNA templates, providing a safer editing approach.

• On 21 June 2016, the NIH approved the first clinical trial using CRISPR-Cas9 to treat patients, led by researchers at the University of Pennsylvania, focusing on gene therapy and cancer immunotherapy.

• In February 2017, the US National Academies of Science and Medicine endorsed proceeding with CRISPR in germline experiments, allowing cautious progress in inheritable gene editing research.

• On 13 April 2017, Abudayyeh, Bhattacharyya, Collins, and others from Broad Institute, MIT, Harvard, and Howard Hughes Medical Institute demonstrated CRISPR’s sensitivity as a diagnostic tool capable of detecting single DNA or RNA molecules.

• On 13 May 2017, Yin, Zhang, Qu, and colleagues from Temple University, University of Pittsburgh, and Sichuan University published research demonstrating CRISPR-Cas9 can eliminate HIV in infected mice, advancing antiviral gene therapy.

• On 2 August 2017, Hong, Marti-Gutierrez, Park, Mitalipov, Kaul, Kim, Amato, and Belmonte from multiple institutions showed gene editing in pre-implanted human embryos to prevent inherited heart disease, marking progress in reproductive gene editing and cardiovascular genetics.

• In September 2017, scientists Fogarty, McCarthy, Snijders, Powell, and others from Francis Crick Institute, Cambridge University, Oxford University, and Seoul National University edited the DNA of human embryos using CRISPR-Cas9 to study infertility causes, contributing to reproductive genetics research.

• On 23 September 2017, Chinese researchers Liang, Ching, Sun, Xie, Xu, Zhang, Xhiong, Ma, Liu, Wang, Fang, Songyang, Zhou, and Huang at Sun Yat-sen University and Baylor College of Medicine reported correction of the gene linked to beta thalassemia, an inherited blood disorder, in human embryos using the base editing technique.

• On 25 October 2017, Zhang, Cox, Gootenberg, Abudayyeh, B Franklin, Kellner, Essletzbichler, Verdine, Joung, Lander, Belanto, Voytas, and Regev at MIT and University of Minnesota published a new CRISPR technique for editing RNA, expanding gene editing beyond DNA.

• On the same day, Gaudelli, Komor, Rees, Packer, Badran, Bryson, and Liu from MIT and Harvard University announced improvements in base editing for CRISPR, enabling precise changes to individual chemical bases of DNA without cleaving DNA strands.

• On 5 January 2018, Charlesworth, Deshpande, Dever, Dejene, Gomez-Ospina, Mantri, Pavel-Dinu, Camarena, Weinberg, and Porteus from Stanford University identified pre-existing human antibodies targeting Cas9 proteins, raising concerns about immune responses that could limit CRISPR-Cas9 gene therapy efficacy.

• On 27 August 2018, the first CRISPR-Cas9 clinical trial was launched by Vertex Pharmaceuticals and CRISPR Therapeutics, marking a major milestone in applying gene editing in human therapy.

• On 24 November 2018, Chinese scientist Jiankui from Southern University of Science and Technology of China announced the birth of the first gene-edited babies, sparking widespread ethical controversy.

• On 14 December 2018, Matharu, Rattanasopha, Tamura, Maliskova, Wang, Bernard, Hardin, Eckalbar, Vaisse, and Ahituv at University of California San Francisco developed CRISPRa, a gene modification technique that increases expression of target genes rather than editing DNA sequence.

• On 21 December 2018, Kmiec, Bialk, Wang, and Hanas at Helen F Graham Cancer Center demonstrated CRISPR-Cas9 editing restored the effectiveness of first-line chemotherapies for lung cancer, showing applications in oncology.

• On 23 January 2019, Grunwald, Gntz, Poplawski, Xu, Bier, and Cooper at University of California San Diego used CRISPR-Cas9 to control genetic inheritance in mice, advancing research in genetics and transgenic animals.

• On 21 October 2019, Anzalone, Randolph, Davis, Sousa, Koblan, Levy, Chen, Wilson, Newby, Ranguram, and Liu at MIT and Harvard published the ‘prime editing’ technique, a new DNA editing method that improves precision and expands gene editing capabilities.

• On 30 December 2019, Chinese scientist Jiankui was convicted for unethical use of CRISPR-Cas9 to edit genes in human babies, highlighting regulatory and ethical challenges in gene editing.

• On 4 March 2020, Pennesi at Oregon Health and Science University administered gene editing therapy using CRISPR directly into a patient’s body for the first time, marking a clinical application breakthrough.

• In June 2020, research from Francis Crick Institute, Columbia University, and Oregon Health & Science University raised safety concerns about using CRISPR-Cas9 to modify human embryos, emphasizing need for caution.

• On 7 October 2020, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for developing the CRISPR-Cas9 genome editing method, recognizing its transformative impact.

• On 27 September 2022, the FDA granted Vertex Pharmaceuticals approval to submit rolling applications to review CRISPR-based therapies for treating sickle cell disease and beta thalassemia.

• On 10 November 2022, a small clinical trial led by Foy, Ribas, and Mandl at PACT Pharma demonstrated CRISPR’s promise in editing immune cells to enhance their cancer-killing abilities.

• On 23 November 2022, Al-Shayeb, Skopintsev, Soczek, Stahl, Zheng Li, Smock, Eggers, Pausch, Cress, Huang, Staskawicz, Savage, Jacobsen, Banfield, and Doudna at University of California Berkeley discovered new CRISPR gene editing tools in thousands of bacteriophages, expanding the diversity of CRISPR systems.

• On 15 November 2023, the world’s first CRISPR-Cas9 gene editing therapy received conditional approval in the UK for treating two blood disorders, developed by Vertex Pharmaceuticals and CRISPR Therapeutics.

• On 6 May 2024, Eric A. Pierce and collaborators at Harvard University, University of Pennsylvania, and Editas Medicine reported promising results from a phase 1/2 trial using CRISPR gene therapy for inherited vision loss.