The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

by Walter Isaacson

the meantime, Jinek worked on ways to turn the single-guide RNA that they had devised in test tubes into a guide that could get Cas9 to the right target in a human cell.

When trying to move a gene-expression system from one organism to another, such as from bacteria to a human, codon optimization switches the codon sequence to the one that works

using CRISPR-Cas9 in human cells. That

Lander

accuses Church of starting his own work on CRISPR only after Zhang told him he was embarked on that task.

Church and Zhang ended up in a virtual tie in showing how CRISPR-Cas9 could be engineered for use in human cells.

His version was longer than the one Zhang devised and ended up working even better.

though Charpentier had not wanted to collaborate on the effort to edit human cells, she felt a little proprietary about the CRISPR-Cas9 system.

Others—such as the invention of the microchip and the application of CRISPR to editing human cells—were accomplished by many groups at around the same time.

the fact that five different papers on CRISPR-Cas9 editing in animal cells all appeared in January 2013 reinforced the argument that this discovery was inevitable after it had been shown that it could work in a test tube.

Church’s bushy beard and cultivated eccentricities continued to make him a scientific celebrity, and on the day of the meeting that caused him to be distracted. In an interview with the German magazine Spiegel, he had offhandedly speculated about the possibility of resurrecting a Neanderthal by implanting its DNA in the egg of a volunteer surrogate mother. Not surprisingly (except perhaps

The decision not to pool the CRISPR-Cas9 intellectual property would pave the way for an epic patent battle.

They were all brilliant but had an even more important trait: “They were the people who do good science but are more importantly honorable straight-shooters.”

a result, the pioneers of CRISPR-Cas9 ended up in three competing companies: CRISPR Therapeutics, founded by Charpentier and Novak; Editas Medicine, which included Zhang and Church and Doudna until she resigned; and Intellia Therapeutics, which included Doudna, Barrangou, Sontheimer, Marraffini, and Haurwitz.

There was another underlying reason for the strain: from Doudna’s perspective, she was an equal co-discoverer of the CRISPR-Cas9 system, but Charpentier viewed CRISPR-Cas9 as her own project,

Doudna never quite understood Charpentier’s proprietary feelings

Almost every person in any saga tends to remember their own role as being a little more important than the other players see it.

As Charpentier views the CRISPR narrative, she was the one who first worked on Cas9, identified its components, and then brought Doudna into the project.

tracrRNA,

sticks around to help the CRISPR-Cas9 complex cleave the targeted DNA.

tracerRNA

After they published the paper, Charpentier would occasionally suggest that she knew about the ongoing role of tracrRNA back in 2011, before she started collaborating with Doudna. This began to annoy Doudna.

and I think that’s disingenuous, it’s untrue,”

One of the largest and most glamorous of these awards, the Breakthrough Prize in Life Sciences, was given to Doudna and Charpentier as a pair in November 2014,

was skewed, in ways both subtle and heavy-handed, to tout the contributions of Zhang and minimize those of Doudna.

Yet the article clearly had another thrust, one that was done with a velvet glove but was nonetheless an unmistakable diminishment of Doudna.

Eric Lander is an evil genius at the height of his craft,”

Michael Eisen, Doudna’s colleague at Berkeley. He believes that the government should put all work funded by federal dollars into the public domain. “We all would benefit returning academic science to its roots in basic discovery oriented research. We see with CRISPR the toxic effects of turning academic institutions into money hungry hawkers of intellectual property.”2

May 25, 2012,

December 2012,

respectfully question the origin of the example,” Zhang said. In one of their legal filings, Zhang and the Broad asserted, “It was only after the Church laboratory shared unpublished data that Dr. Doudna’s laboratory reported they were able to adapt a CRISPR-Cas9 system” for use in human cells. Doudna was outraged at Zhang’s declaration because it implied that she had plagiarized Church’s data. She called Church at his home on a Sunday afternoon, and he shared her anger

the distorting effects that patent law can have on scientific collaboration.

It’s also a tale of competitiveness, perhaps even greed, overwhelming kindness, and collegiality.

Therein lies one of the problem with patents: they prod people to be less generous in sharing credit.

Even though her team’s experiments had involved bacteria, she argued that their patent application “specifically states” that the system can be applied in “all organisms” and provides “detailed descriptions of numerous steps that could be taken to apply the system” to humans.14 Zhang argued in his response declaration that Doudna’s application “did NOT [emphasis in the original] have the features required for Cas9 binding and DNA target site recognition in a human cell.”15

Doudna and her colleagues had identified the essential components of CRISPR-Cas9 and engineered a technique to make it work using components from bacterial cells.

Their contention was that it was then “obvious” how it would w...

“obvious”

a term of art.

Unfortunately, phrases such as “person of ordinary skill” and “reasonable likelihood of success” are fuzzy when applied to biology,

eukaryotic

cell with a nucleus

We weren’t sure if CRISPR-Cas9 would work in plant and animal cells.”

However, it was not known whether such a bacterial system would function in eukaryotic cells.”

Five labs had made the system work in eukaryotic cells within six months of the publication of the Doudna-Charpentier discovery, he said, which was an indication of how “obvious” such a step was.

Zhang was entitled to his patent; it did not interfere with Doudna and Charpentier’s application.

Because there was “no interference” between the two sets of applications, they could be considered separately, which meant that it was still possible that the Doudna-Charpentier application would be granted as well.

is not a ruling on the validity of either set of claims.”

early 2019, the U.S. Patent Office granted fifteen patents based on the applications that Doudna and Charpentier had filed in 2012.

which side had made the key discoveries first.

The patent that was granted to Doudna and Charpentier was for the use of CRISPR-Cas9 in all organisms, from bacteria to humans.

their patent application, when considered in its entirety, described how to use the system in any organism.