CRISPR/CAS9 patent fight spreads gobally, are you ready?

Injecting a bottle of foreign DNA to obtain extra power has been a popular theme in many science fictions and films. This ain’t no fuckin fiction, it is reality. The biggest biotech discovery of the century, CRISPR/CAS9, makes it possible.

The CRISPR/CAS9 system is emerging as a powerful site-specific gene editing tool. This breakthrough technology allows scientists to precisely and easily perform microsurgery on genes at exact sites. The discovery of CRISPR/CAS9 is absolutely going to be the subject of a Nobel prize.

Here is the timeline of the CRISPR/CAS9 technology.

1987: CRISPRs were first discovered in the genome of Escherichia coli[1].

2000: CRISPRs were detected in archaea, bacteria and mitochondria[2].

2005: Spacer sequences within CRISPRs are derived from foreign DNA[3-5].

2006-2007: CRISPR/CAS is a prokaryotic adaptive immune system[6-7].

2010: CRISPR/CAS cuts target DNA[8].

2011: tracrRNA directs the maturation of crRNAs[9].

2012: Programmable crRNA:tracrRNA duplex directs CAS9 cleavage[10].

2012: Several CRISPR/CAS9 patent applications were filed.

2013: CRISPR/CAS9 simultaneously edits multiplex genome in human cells[11].

2013-2014: Generation of animal models by CRISPR/CAS9[12-15].

2013-2014: Editas Medicine and CRISPR Therapeutics were founded.

2014: Structures of CAS9 reveals RNA-mediated conformational activation[16].

2014: CRISPR/CAS9 knockout screening in human cells[17-18].

2014: CRISPR/CAS9 corrects gene mutation in mouse model[19].

2014: First CRISPR/CAS9 patent was granted.

In April 2014, the Broad Institute and MIT have been awarded the first CRISPR/CAS9 patent (US8697359) in the US. Editas Medicine, co-founded by Feng Zhang (张锋), licensed the patent from the Broad Institute and raised $43 million from Third Rock Ventures, Polaris Partners, and Flagship Ventures in series A financing.

CRISPR Therapeutics, another biotech company focused on the CRISPR/CAS9 technology raised $25 million in a series A investment from Versant Ventures. Emmanuelle Charpentier, a co-founder and advisor to the company, has been awarded the 2015 Breakthrough Prize in Life Sciences. The company invited Nobel laureate and RNA interference pioneer Craig Mello as a scientific founder.

The CRISPR/CAS9 patent fight has spread from the US to Europe[21-22]. Here are CRISPR/CAS9 patent applications from Editas Medicine and CRISPR Therapeutics.

Publication Inventor Title Priority date
WO2013176772 Emmanuelle Charpentier Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription 2012-05-25
WO2014093661 Zhang Feng CRISPR-CAS systems and methods for altering expression of gene products 2012-12-12
WO2014022702 Jennifer Doudna Methods and compositions for controlling gene expression by RNA processing 2012-08-03

In March 2014, MIT’s scientists reported the first use of CRISPR/CAS9 to correct gene mutation in adult mammals[19]. Hydrodynamic injection of the CRISPR/CAS9 system in a mouse model of hereditary tyrosinemia with FAH mutation resulted in initial expression of the wild-type FAH protein in 0.4% liver cells. This represents the first demonstration of the potential utility of the CRISPR/CAS9 system as a therapeutic strategy in vivo.

However, hydrodynamic injection could not be straightforwardly used in human. Just like other RNA/DNA therapies, the biggest hurdle for CRISPR/CAS9 is delivery of such delicate system to the right organs and cells. The second concern is the high-frequency off-target mutagenesis induced by CRISPR/CAS9 in human cells[20]. Using CRISPR/CAS9 to treat stem cells first and then injecting the corrected stem cells back into patients may avoid both these problems.

Currently, the CRISPR/CAS9 technology is mainly used in the establishment of animal models and knockout screening. What I care about is the potential to correct gene mutations that cause various genetic disorders. In the future, systematic integration of foreign genes using CRISPR/CAS9 may generate ingenious scientists, powerful warriors, and pretty girls in batches.

[1] J Bacteriol. 1987, 169(12), 5429-5433.

[2] Mol Microbiol. 2000, 36(1), 244-246.

[3] Microbiology. 2005, 151(Pt 8), 2551-2561.

[4] Microbiology. 2005, 151(Pt 3), 653-663.

[5] J Mol Evol. 2005, 60(2), 174-182.

[6] Biol Direct. 2006, 1, 7.

[7] Science. 2007, 315(5819), 1709-1712.

[8] Nature. 2010, 468(7320), 67-71.

[9] Nature. 2011, 471(7340), 602-607.

[10] Science. 2012, 337(6096), 816-821.

[11] Science. 2013, 339(6121), 819-823.

[12] Nature. 2014, 514(7522), 380-384.

[13] Cell. 2013, 153(4), 910-918.

[14] Cell. 2014, 156(4), 836-843.

[15] Nat Biotechnol. 2014, 32(9), 941-946.

[16] Science. 2014, 343(6176), 1247997.

[17] Science. 2014, 343(6166), 84-87.

[18] Nature. 2014, 509(7501), 487-491.

[19] Nat Biotechnol. 2014, 32(6), 551-553.

[20] Nat Biotechnol. 2013, 31(9), 822-826.

[21] Nat Biotechnol. 2014, 32(7), 599-601.

[22] Nat Biotechnol. 2014, 32(12), 1194-1196.

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