Found in Translation

Antibodies Part 3: In whose corner is genome editing’s best cut-man sitting?


 

We are in the midst of a revolution in genome editing. Science now exists in “AC,” or after CRISPR. Able to speedily and efficiently make genomic cuts with surgical precision, CRISPR/Cas9 is used almost ubiquitously now in the scientific community to study and alter DNA across fields ranging from medicine to agriculture to zoology. The possibilities of the biological and therapeutic implications are seemingly endless, as are the important ethical implications of their impact. Likely because of the latter, CRISPR technology has made its way from publications like Science and Nature into the lay public domains of Newsweek and NBC News.

In fact, CRISPR technology made its way into one of my favorite podcasts, WNYC’s “Radio Lab” in June 20151. The episode was entitled “Antibodies Part 1,” perhaps assuming that other technologies would also be discussed later although that has never happened. Actually, in an update early this year, the podcast jokingly addressed never moving on to “Part 2,” then followed with an update on how far CRISPR technology has progressed. Putting aside the technological advances and the early clinical applications, as well as the immense ethical considerations, CRISPR technology faces a new controversy, not one from a white coat but rather from a black robe.

Dr. Aaron Viny of Memorial Sloan-Kettering Cancer Center, New York

Dr. Aaron Viny

This past December, the U.S. Patent and Trademark Office (USPTO) heard testimony over a CRISPR patent dispute, which centered on Jennifer Doudna, PhD, at the University of California, Berkeley, and Feng Zhang, PhD, at the Broad Institute, Cambridge, Mass. Both investigators have pioneered using the CRISPR/Cas9 system in their respective published work and each of their institutions have applied for patents to protect the application of the technology for scientific and therapeutic applications.

In her CommonHealth blog2, Carey Goldberg of WBUR Boston Public Radio compared the case with the bout between undefeated Muhammad Ali and undefeated Joe Frazier at New York’s Madison Square Garden. Both men had legitimate claims to the title of World Heavyweight Champion. What transpired is now known as the “Fight of the Century.”

The analogy is apt. Boxing is about speed and control. Ali dominated the first three rounds with his jab, a punch that is both offensive with its attack and defensive in keeping one’s opponent at a distance. Dr. Doudna and her collaborator Emmanuelle Charpentier, PhD, published their work first (Science. 2012 Aug 17;337[6096]:816-21)3. UC Berkeley filed their patent first in May 2012.

Boxing is about timing and opportunity. Under the barrage of Ali’s jabs, Frazier found an inside position and caught Ali with a left hook. Dr. Zhang’s work followed closely after but had previously applied the technology in murine and human cells (Science. 2013 Feb 15; 339[6121]:819-23)4. The Broad Institute used this key difference to apply for its own patents under expedited review, which were granted in April 2014.

Boxing is about a punch and a counterpunch. Though fatigued, Ali continued to connect with combination punches. Frazier’s left hook pummeled Ali’s jaw. UC Berkeley filed an interference motion to invalidate the Broad Institute patent claim on the basis that the extension to eukaryotic cells was “obvious” based on the published work by Dr. Doudna’s group. In February, USPTO ruled that the Broad patent application may proceed, citing “patentably distinct subject matter.” Initial reports had indicated that Berkeley may appeal the decision, but no official filings have been made public.

Like the Fight of the Century, this case may go the distance and be decided by the judges. In a unanimous decision, Joe Frazier won the first of three epic bouts. The final scorecard is not known in the patent disputes; on March 28, the European Patent Office announced it will grant the patent application on behalf of Dr. Doudna and Dr. Charpentier.

Much like a prizefight, Wall Street has also been taking bets on who will prevail, with CRISPR-based biotech backing both sides mirroring the mid-bout odds, just as Ali dominated early with the jab, until Frazier evened the match with a left hook to the jaw. Ali fell to his knee on the canvas in the 11th round; will the European Patent Office decision prove to be a slip or a decisive knockdown? With so much at stake, the only assurance is that, as with the Ali-Frazier bout, there is likely more fighting to be done.

References:

1. Radio Lab

2. CommonHealth blog

3. Jinek M, et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012 Aug 17;337(6096):816-21.

4. Le Cong et al., Multiplex genome engineering using CRISPR/Cas Systems. Science. 2013 Feb 15;339(6121):819-23. Multiplex genome engineering using CRISPR/Cas Systems.

Science. 2017 Feb 15: Round one of CRISPR patent legal battle goes to the Broad Institute.

StreetInsider.com: CRISPR Therapeutics (CRSP) says EPO to grant CRISPR/Cas gene editing patent.

On Twitter @thedoctorisvin

Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.

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