Pivotal & Recent Developments in Gene Editing

L. Val Giddings, Ph.D. 
Senior Fellow, Information Technology & Innovation Foundation

Hardly a day goes by without new reports of advances in gene editing. It can be very hard to keep up, even for those following closely. This compilation brings together a list of salient events and media coverage over the last three decades. It is not complete or encyclopedic, but eclectic, focused primarily on CRISPR, and, we hope, illuminating. It will be updated as developments warrant.

Note: This timeline was last updated on January 15, 2019.

1987: Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. Ishino Yoshizumi, Shinagawa H, Makino K, Amemura M, Nakata A. 1987. J Bacteriol 169:5429–5433. doi:10.1128/jb.169.12.5429–5433.1987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC213968/.

This is the first published report documenting the existence in E. coli of an unusual repeating sequence of DNA of unknown function, later determined to be CRSIPR, and subsequently found widely among bacteria.

2007: CRISPR provides acquired resistance against viruses in prokaryotes. Barrangou R1, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P. Science. 2007 March 23; 315(5819):1709–12. http://science.sciencemag.org/content/315/5819/1709/tab-pdf.

Danisco scientists discover that the unusual repeats are part of a bacterial defense system against viruses, and figure out how to harness it for use in yoghurt production.

2008 19 December: CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA http://science.sciencemag.org/content/322/5909/1843.long.

An early intimation of practical applications of CRISPR, in this case to limit the spread of antibiotic resistance under specific circumstances.

2012: A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Jinek M1, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. Science. 2012 Aug 17;337(6096):816–21. doi: 10.1126/science.1225829. Epub 2012 Jun 28. https://sci-hub.tw/10.1126/science.1225829.

This is the keystone paper that finally put all the pieces together in figuring out how CRISPR works and how it might be used, by virtue of which Charpentier & Doudna are widely assumed to be front runners for a Nobel.

2015 4 June: HeidiLedford CRISPR, the disruptor: A powerful gene-editing technology is the biggest game changer to hit biology since PCR. But with its huge potential come pressing concerns. Nature 522, 20–24 http://www.nature.com/news/crispr-the-disruptor-1.17673.

2016 22 June: Sara Reardon First CRISPR clinical trial gets green light from US panel Nature doi:10.1038/nature.2016.20137 https://www.nature.com/news/first-crispr-clinical-trial-gets-green-light-from-us-panel-1.20137.

“…an advisory committee at the US National Institutes of Health (NIH) approved a proposal to use CRISPR–Cas9 to help augment cancer therapies that rely on enlisting a patient’s T cells, a type of immune cell.”

21 July: David Cyranoski Chinese scientists to pioneer first human CRISPR trial — Gene-editing technique to treat lung cancer is due to be tested in people in August Nature 535, 476–477 doi:10.1038/nature.2016.20302 http://www.nature.com/news/chinese-scientists-to-pioneer-first-human-crispr-trial-1.20302.

2017 14 February: U.S. National Academies of Sciences, Engineering & Medicine Human Genome Editing: Science, Ethics, and Governance. https://www.nap.edu/catalog/24623/human-genome-editing-science-ethics-and-governance.

This thoughtful and thorough NAS report lays a solid groundwork for the responsible and ethical pursuit of gene editing applied to humans. It anticipated and described measures for preventing the kind of abuses manifest in He Jiankui’s approach.

2018 28 March: USDA Secretary Perdue Issues USDA Statement on Plant Breeding Innovation https://www.usda.gov/media/press-releases/2018/03/28/secretary-perdue-issues-usda-statement-plant-breeding-innovation

USDA announces they will not regulate gene edited innovations that mimic traits found naturally in plants and animals.

27 April: Retraction: “Unexpected mutations after CRISPR–Cas9 editing in vivo” Nature Methods vol 5, page 394 (2018). https://www.nature.com/articles/nmeth0518-394a.

This announcement retracts a paper widely publicized for its claim of numerous non target side effects from gene editing. The results of the original paper could not be repeated by the original authors or other labs, mooting a potentially significant cause for safety concerns.

31 May: UK plants its first gene edited crop (Camelina). https://allianceforscience.cornell.edu/blog/2018/05/uk-plants-first-gene-edited-crop/.

“Scientists at Rothamsted Research have sown one of the world’s first experimental field trials of a genome edited crop in an effort to develop more nutritious plants that can be sustainably grown.”

31 May: Paul Vincelli Are Non-Target Mutations via CRISPR in Plants a Concern? https://vincelliblog.wordpress.com/2018/05/31/are-non-target-mutations-via-crispr-in-plants-a-concern/.

1. In plants, reported off-target rates are commonly low to non-existent [1–13]; 2. Strategies for reducing off-target mutations continue to be researched and published [9, 13–20]; 3. Off-target mutations can be monitored via whole-genome sequencing; 4. In sexually reproducing crops, undesirable mutations can be segregated out [15]; 5. In contrast to clinical applications in humans, the relevance of non-target genetic changes during crop improvement is questionable.

4 July: A large-scale whole-genome sequencing analysis reveals highly specific genome editing by both Cas9 and Cpf1 (Cas12a) nucleases in rice. https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1458-5.

“Our comprehensive and rigorous analysis of WGS data across multiple sample types suggests both Cas9 and Cpf1 nucleases are very specific in generating targeted DNA modifications and off-targeting can be avoided by designing guide RNAs with high specificity.”

6 July: Controversial CRISPR ‘gene drives’ tested in mammals for the first time (lab mice). https://www.nature.com/articles/d41586-018-05665-1.

“…researchers describe developing ‘gene drives’ — which could be used to eradicate problematic animal populations — in lab mice using the CRISPR gene-editing technique.”

11 June: CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. https://www.nature.com/articles/s41591-018-0049-z. Researchers report results suggesting CRISPR might be useful to impact one of the main genes important in the development of cancer in humans.

11 July: Gene editing in Macaque model results in high cholesterol treatment (meganucleases). http://bioscriptionblog.com/2018/07/11/gene-editing-macaque-high-cholesterol/.

16 July, 2018: Nuffield Council on Bioethics: Genome editing and human reproduction: Social and Ethical Issues. http://nuffieldbioethics.org/project/genome-editing-human-reproduction.

The reliably credible and independent Nuffield Council has navigated complicated moral thickets on many challenging issues. This landmark contribution extends their excellent record and provides appropriate yardsticks for evaluating and considering human gene editing.

23 July: A simple guide to CRISPR, one of the biggest science stories of the decade. https://www.vox.com/2018/7/23/17594864/crispr-cas9-gene-editing.

A user friendly guide to CRISPR in the popular media!

25 July: European Court of Justice ruling on gene editing. https://curia.europa.eu/jcms/upload/docs/application/pdf/2018-07/cp180111en.pdf.

This (widely condemned) ECJ ruling decided that products of gene editing would be legally subject to the draconian EU regulations applied to “GMOs” which are widely recognized as unscientific, impermissibly discriminatory, and disincentivizing to innovation.

3 August: CRISPR-Cas12a More Precise Than CRISPR-Cas9. https://www.genengnews.com/topics/genome-editing/crispr-cas12a-more-precise-than-crispr-cas9/81256099/?utm_medium=newsletter.

Paper describing details of a CRISPR gene editing mechanism with a different functionality than Cas9 (one of many), making it a superior tool for some applications.

6 August: Gene-edited silkworms spin out spider silk, could lead to mass production https://www.digitaltrends.com/cool-tech/gene-edited-spider-silk/.

20 August: Scientists tweak DNA in viable human embryos (Marfan synbdrome). https://www.sciencemag.org/news/2018/08/scientists-tweak-dna-viable-human-embryos.

“Researchers from China used a variation of CRISPR… to correct a single amino acid that causes Marfan syndrome, a connective tissue disorder that can affect the heart, bones, and joints.”

24 August: A CRISPR cure for Duchenne muscular dystrophy is closer after a trial in dogs. Treating a fatal muscle disease could be the next major advance for gene editing. https://www.technologyreview.com/s/611940/a-crispr-cure-for-duchenne-muscular-dystrophy-trial-in-dogs-exonics/.

31 August: First CRISPR clinical trial backed by U.S. companies launches. https://www.statnews.com/2018/08/31/human-trial-of-crispr-for-blood-disorder-launches/?utm_content=buffere644f&utm_medium=social&utm_source=twitter&utm_campaign=twitter_organic.

“The first clinical trial of CRISPR-Cas9 sponsored by U.S. companies has launched, testing the genome-editing technique in patients with the blood disorder beta thalassemia…”

4 September: CRISPR halts fatal genetic disease in dogs, could soon do the same in humans. https://www.digitaltrends.com/cool-tech/crispr-gene-editing-dmd/

“…scientists were able to use a single-cut gene-editing technique to restore” normal levels of a key protein, the absence of which causes a fatal genetic disease known as Duchenne muscular dystrophy.

5 September: First test of in-body gene editing shows promise (Hunter syndrome). Preliminary results suggest that treatment for rare disease is safe, but its effectiveness is unclear. https://www.nature.com/articles/d41586-018-06195-6

10 September: Heidi Ledford UC Berkeley vs Broad Institute patent litigation: Team from the University of California, Berkeley, loses appeal over coveted gene-editing technology. https://www.nature.com/articles/d41586-018-06656-y.

Once anticipated as a ruling that would make or break emerging commercial empires, the impact of this decision has been attenuated by rapid pace of scientific progress in understanding CRISPR (see, e.g., the entry for 3 August).

12 September: Kansas Wheat Commission to Fund Gene Editing Research at Kansas State University https://seedworld.com/kansas-wheat-commission-to-fund-gene-editing-research-at-kansas-state-university/.

With wheat growers alarmed at dwindling competitiveness caused by missing out on the transgenic revolution, “The Kansas Wheat Commission has announced that it is putting its support behind a technology… that one researcher says will bring “many new discoveries” in improving wheat.”

21 September: Bacterial Immunity — Anti-CRISPR RNA? http://science.sciencemag.org/content/361/6408/1212.6

Mother Nature is not only stranger than we imagine, it is stranger than we can imagine. “Bacteria use the CRISPR-Cas immune system to fend off viruses; viruses use anti-CRISPR proteins to fight back. Some bacteria have acquired anti-CRISPR proteins in their genomes to avoid self-cutting. Meeske and Marraffini report the intriguing possibility that bacteria might also use RNA to inhibit CRISPR-Cas enzymes.”

28 September: Editing mosquito DNA could help wipe out malaria and Zika — here’s how https://www.digitaltrends.com/cool-tech/mosquito-gene-drive-dna-ending-population/.

“Researchers from the United Kingdom’s Imperial College London have developed a new, promising approach to add to the toolset: A “gene drive” which disseminates a genetic modification that stops female mosquitoes from reproducing.”

28 September: Roseville gene-editing firm Calyxt announces deal with soybean processor — The high-tech soybeans have been stripped of the gene that creates trans fats. http://www.startribune.com/roseville-gene-editing-firm-calyxt-announces-deal-with-soybean-processor/494629061/.

3 October: Japan set to allow gene editing in human embryos — Draft guidelines permit gene-editing tools for research into early human development. https://www.nature.com/articles/d41586-018-06847-7.

“Japan has issued draft guidelines that allow the use of gene-editing tools in human embryos.”

4 October: Domesticating crops usually takes centuries. CRISPR just did it in two years. https://www.digitaltrends.com/cool-tech/gene-editing-crispr-groundcherries/.

“… technology-aided rapid “domestication” could mean transforming the little-known groundcherries into agriculture’s next mainstream berry crop.”

7 November: 13 nations say it’s time to end ‘political posturing’ and embrace crop gene editing. https://geneticliteracyproject.org/2018/11/07/13-nations-say-its-time-to-end-political-posturing-and-embrace-crop-gene-editing/.

“How would the rest of the world react to the polar opposite positions established by the EU and the US. We are now getting some clarity. A coalition of 13 countries announced this week that it would “support policies that enable agricultural innovation, including genome editing.””

11 October: FDA gives go-ahead for CRISPR-based sickle cell disease trial. https://pharmaphorum.com/news/fda-gives-go-ahead-for-crispr-based-sickle-cell-disease-trial/.

“Development of a stem cell therapy for sickle cell disease from Vertex and development partner CRISPR therapeutics can go ahead, after the FDA lifted a hold on a review.”

8 November: Ginkgo Bioworks and Glycosyn LLC Announce $14MM Deal to Scale Production of Human Milk Oligosaccharides. https://synbiobeta.com/news/ginkgo-bioworks-and-glycosyn-human-milk-oligosaccharides/?utm_content=buffer43388&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer.

Companies announce a joint effort “to optimize and scale the production of human milk oligosaccharides (hMOS) for a suite of products that offer health benefits by fostering a healthy gut microbial ecology.”

11 November: Elo Life Systems Launches Australian Subsidiary in Queensland. https://synbiobeta.com/news/elo-life-systems-launches-australian-subsidiary-in-queensland/?utm_content=buffer47b3c&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer.

Australian company aims to use gene editing to develop “novel plant-based protein alternatives and other nutritionally enhanced crops that bolster Australia’s position as a leading global exporter of high protein pulses.”

25 November: Antonio Regalado EXCLUSIVE: Chinese scientists are creating CRISPR babies-A daring effort is under way to create the first children whose DNA has been tailored using gene editing. https://www.technologyreview.com/s/612458/exclusive-chinese-scientists-are-creating-crispr-babies/.

The story that broke the announcement of He Jiankui’s paradigm shifting claims.

SEE EXPANDED TIMELINE ON CRISPR BABIES AT THIS LINK.

28 November: Nature Editorial: Fear holds back gene-edited crops — educate the public. https://www.nature.com/articles/d41586-018-07547-y.

6 December: Japan may boost gene-edited foods development https://english.kyodonews.net/news/2018/12/66a6cf039c8d-panel-report-may-help-promote-gene-edited-foods-in-japan.html

“A health ministry panel said… most of the foods currently under development using genome editing can be marketed without safety screening by the state, a proposal that would accelerate the creation of such items as more nutritious tomatoes and more meaty red seabream in Japan.”

12 December: Rice Plants That Reproduce as Clones From Seed: Ability to Grow Hybrid Varieties a Potential Breakthrough for Global Agriculture. By Andy Fell in Food & Agriculture https://www.ucdavis.edu/news/rice-plants-reproduce-clones-seed.

“Plant biologists at the University of California, Davis, have discovered a way to make crop plants replicate through seeds as clones. The discovery, long sought by plant breeders and geneticists, could make it easier to propagate high-yielding, disease-resistant or climate-tolerant crops and make them available to the world’s farmers.”

14 December: CRISPR without the Chop Reverses Genetic Obesity in Mice. https://www.genengnews.com/news/crispr-without-the-chop-reverses-genetic-obesity-in-mice/.

Scientists at UCSF have reversed two kinds of obesity in mice not by changing DNA sequences but by using “CRISPR activation (CRISPRa)” to elevate production of native compounds.

14 December: Preetika Rana and Lucy Craymer Deformities Alarm Scientists Racing to Rewrite Animal DNA-Unintended consequences have included enlarged rabbit tongues and extra pig vertebrae, as bioethicists warn of hubris. https://www.wsj.com/articles/deformities-alarm-scientists-racing-to-rewrite-animal-dna-11544808779.

A substandard piece that mistakenly suggests dangers from gene editing by citing pathologies well known for decades to be side effects of animal cloning.

17 December: Carolyn Y. Johnson Gene-edited farm animals are coming. Will we eat them? Cutting-edge lab techniques could improve animal breeding, but society may not be ready. https://www.washingtonpost.com/news/national/wp/2018/12/17/feature/gene-edited-farm-animals-are-coming-will-we-eat-them/?utm_term=.d152dfa9a772

This is a well written, factually accurate roundup of the state of play re gene editing in livestock.

18 December Jean-Denis Faure & Johnathan A Napier Point of View: Europe’s first and last field trial of gene-edited plants? https://elifesciences.org/articles/42379

British researchers recount the first UK field trial of a CRISPR-Cas9 edited plant and predict the ECJ decision to apply EU GMO regulation may also make it the last.

18 December Intrexon and AquaBounty Receive Regulatory Exemption in Development of Gene Edited Tilapia for More Sustainable Production — Assessment by Argentina’s National Advisory Commission on Agricultural Biotechnology Sets Regulatory Precedent. https://www.prnewswire.com/news-releases/intrexon-and-aquabounty-receive-regulatory-exemption-in-development-of-gene-edited-tilapia-for-more-sustainable-production-300768053.html.

“This line of tilapia enables more sustainable production through improvements in fillet yield, growth and feed conversion efficiency, enabling the tilapia to grow to market weight in less time, while also consuming less feed than conventional varieties.”

21 December Jesse Kirkpatrick & Michael Flynn Don’t Let Russia Undermine Trust in Science — Disinformation around genetic editing could set back advances to improve both health and the economy. https://slate.com/technology/2018/12/russia-science-disinformation-genetic-editing-crispr-social-media.html

In a recent report on security and genome editing, we outline how a weaponized narrative on gene drive technology could unfold as part of a sophisticated information warfare campaign… But a healthy dose of user skepticism may help mitigate the risk of weaponized bionarratives damaging important scientific advances.

4 January 2019 Jonathan Shieber Up to $818 million deal between J&J and Locus Biosciences points to a new path for CRISPR therapies. https://techcrunch.com/2019/01/04/up-to-818-million-deal-between-jj-and-locus-biosciences-points-to-a-new-path-for-crispr-therapies/.

“The up to $818 million deal… points toward a new path for CRISPR gene editing technologies and (potentially) the whole field of microbiome-targeted therapies… focused on Cas3 proteins, which devour DNA Pac-Man-style, rather than edit it like the more well-known Cas9-based CRISPR technologies…”

7 January Nicola Davis Gene editing could create spicy tomatoes, say researchers; Scientists also looking at altering colour of kiwis and taste of strawberries. https://www.theguardian.com/science/2019/jan/07/gene-editing-could-create-spicy-tomatoes-say-researchers.

9 January, 2019 Farah Hancock The story of genetics and Mt Albert’s forbidden fruit — A controversial new apple created by New Zealand scientists has to be seen to be believed — and has to be eaten offshore. https://www.newsroom.co.nz/2019/01/08/389024/mount-alberts-forbidden-fruit.

The red-fleshed apples developed by Plant and Food Research’s scientist Professor Andrew Allan and his team are so contentious they’re not allowed to eat them in New Zealand. “In the end we had to take them to America.”

9 January, 2019 Bertille Duthoit The five: genetically modified fruit — New varieties created through genetic editing and engineering promise to beat disease, and offer enticing new flavours. https://www.theguardian.com/science/2019/jan/13/the-five-genetically-modified-fruit-edited-bananas-tomatoes.

11 January, 2019 Cornell Alliance for Science Petition to the U.S. Food & Drug Administration: Harmonize US gene-edited food regulations. https://www.gopetition.com/petitions/harmonize-us-gene-edited-food-regulations.html.

NGO advocating science based policy to encourage agricultural innovation rallies interested partners from around the world and calls on FDA to return regulatory policy for gene edited animals to alignment with longstanding U.S. policy and fundamental tenets of risk assessment and management.

15 January, 2019 Ayan Das, Namisha Sharma & Manoj Prasad CRISPR/Cas9: A Novel Weapon in the Arsenal to Combat Plant Diseases Frontiers in Plant Science, 15 January 2019 | https://doi.org/10.3389/fpls.2018.02008.

“The first generation of genome editing technologies, due to their cumbersome nature, is becoming obsolete. Owing to its simple and inexpensive nature the use of CRISPR/Cas9 system has revolutionized targeted genome editing technology. CRISPR/Cas9 system has been exploited for developing resistance against virus, bacteria, and fungi.”