Crispr: Scientists' hopes to win Nobel prize for gene-editing technique at risk over patent dispute

A looming patent dispute threatens to overshadow next week’s announcement and may well scare off the Nobel committee from going anywhere near Crispr-Cas9

University of California, Berkeley Professor of Chemistry Jennifer A. Doudna and Ulmea University Professor and Microbologist Emmanuelle Charpentier (R) speak onstage during the Breakthrough Prize Awards Ceremony

There are no prizes for coming second, at least no Nobel prizes which is why everyone’s eyes will be on Stockholm next week when the greatest accolades in science will be announced.

Hot favourites for the chemistry prize are two scientists widely credited with discovering a revolutionary gene-editing technique that is changing the scientific landscape of everything from genetic medicine to the development of new crops and bio-products.

American Jennifer Doudna and French-born Emmanuelle Charpentier co-authored a key study published in August 2012 that demonstrated the technical power of Crispr-Cas9 to cut and splice genes with extreme efficiency down at the highest resolution possible on the DNA molecule of life.

Since then, Crispr-Cas9 has been shown to work in lifeforms ranging from bacteria, insects and plants to fish, farm animals and humans. It has snowballed into a force that has taken the world of molecular biology by storm, promising new cures, new drugs, and even the possibility of eradicating some inherited diseases by the creation of “genetically modified” babies.

But a looming patent dispute threatens to overshadow next week’s announcement and may well scare off the Nobel committee from going anywhere near Crispr-Cas9 – the committee is notorious for two things; its obsessive secrecy and an institutional aversion to controversy. And the patent row is now making Crispr exceedingly controversial.

While the world’s media have focussed their attention on the contributions of Professor Doudna of the University of California, Berkeley, and Professor Charpentier, now at the Helmholtz Centre for Infection Research in Braunschweig, Germany, the US Patent and Trademark Office has quietly awarded many of the key patents on the Crispr technique to a third scientist, Feng Zhang of the Broad Institute and the affiliated Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

Twitter CEO Dick Costolo, Ulmea Universtiy Professor and Microbologist Emmanuelle Charpentier, University of California, Berkeley Professor of Chemistry Jennifer A. Doudna, and Actress Cameron Diaz attend the Breakthrough Prize Awards Ceremony (Getty)

So far, Professor Zhang and his institute have bagged an impressive portfolio of 13 out of 20 Crispr patents issued by the US patent office – and another four by the European Patent Office. Meanwhile Doudna and Charpentier have been left largely empty handed when it comes to the protection of their intellectual property – and the licensing money that comes with it.

The issue has become so serious that it has pitted the mighty MIT against the equally mighty University of California, with its Berkeley campus openly calling on the US patent office to think again. Earlier this year, the university filed an official request for a “patent interference” which, if allowed, will force the US patent office to decide which academic institution owns the intellectual rights over Crispr in a “winner-takes-all” decision.

The US patent office has yet to respond to our enquiries about whether it intends to grant the review.

Patent disputes of course are nothing new in business. Equally, there has always been competition (as well as collaboration) in science. But when the patent lawyers move in on academia, things can turn personal, especially when tens of millions of dollars are already invested and hundreds more are promised for whoever has control over the key Crispr patents.

Last month, after the Economist magazine put Crispr on its front cover with the headline “The age of the red pen”, a leading figure at the MIT, Robert Desimone, wrote a tart letter disputing the magazine’s assertion that Doudna and Charpentier had “worked out” and demonstrated the gene-editing technique.

“Actually, their [scientific] paper studied the properties of a purified protein in a test tube: it involved no cells, no genomes and no editing. Rather, the paper simply highlighted the potential that genome editing might be possible,” Professor Desimone wrote.

To comprehend what the dispute is about, it is first necessary to understand the nature of the Crispr-Cas9 system. As the name implies, it is made up of two elements. The Crispr part is the programmable molecular machinery that aligns the gene-editing tool at exactly the correct position on the DNA molecule, while the Cas9 is a bacterial enzyme that cuts the DNA rather like a pair of molecular scissors.

Although the discovery of Crispr in bacteria goes back many years, putting it together with Cas9 and getting it to work was the brilliant inventive step of Professor Charpentier and her one-time colleague Professor Doudna. The trouble is, according to the MIT and Broad Institute, the two scientists and Nobel prize favourites only went so far with it.

This is where Professor Zhang comes in. In early 2011, more than a year before Doudna and Charpentier published their paper in Science, Zhang had learned about Crispr at a scientific meeting and immediately realised it was a game-changing technology. At that time, the professor of biomedical engineering at the MIT was just setting up his own research group at the affiliated Broad Institute so he decided to start work on the technique.

Professor Zhang focussed on adapting Crispr, which was essentially a natural gene-editing tool that protects bacteria from viruses, for use in human cells. His key scientific paper came out in January 2013 showing that Crispr-Cas9 can be used to edit the human genome in living cells. As it happened, his paper was published alongside another paper showing much the same thing by Professor George Church at Harvard.

However, Zhang claimed an inventive edge over competing patent claims by producing laboratory notebooks going back to 2011 showing that he was working on the development of a practical use for Crispr-Cas9 in “eukaryotic” cells like those in humans, rather than in the simpler cells of bacteria.

Professor Zhang was unavailable, but the Broad Institute directed us to a prepared statement.

“Zhang’s patent application and published paper included an actual method, one that was the result of nearly two years of independent, focused and successful effort at the Broad Institute and MIT – a method that has since become the standard for genome editing,” the Broad Institute said.

“Broad was not the first to file a patent request related to Crispr. However, Broad was the first to file a patent that described an actual invention – experimental data regarding a successful method for mammalian genome editing,” it said.

It is not possible to patent a natural process, and both Crispr and Cas9 are natural, at least in bacteria. Putting both together and showing how the molecular complex can be used in mammalian cells was the key “inventive step” that the Broad Institute believes swayed the US patent office – but not before the institute instigated a “fast track” patent application to the chagrin of Berkeley’s patent lawyers.

In patent parlance the fast-track is called “accelerated examination” and it meant that although Zhang and his institute applied for patents after Doudna and Charpentier, he was awarded them first. The Broad Institute insisted there is nothing underhand, just that it “simply means” its application was considered more quickly than that of the Berkeley’s.

“It does not change the level of scrutiny applied to the application….In this case, Broad’s applications were considered against those from UC Berkeley and other institutions, as they would have been regardless of whether the patent had been examined via the accelerated review process or otherwise,” the institute said.

But routine or not, it now appears that there is much bad blood flowing in the veins of American academia as a result of the escalating patent row over Crispr-Cas9. And bad feelings between scientists, and especially between their academic institutions, are not going to go down well with the Nobel committee in Stockholm.

Profiles

Feng Zhang is a synthetic biologist and professor of biological engineering at the Massachusetts Institute of Technology. He is also a “core member” of the Broad Institute, which is affiliated to MIT and taking the lead on the patent dispute over the Crispr gene-editing technique. Professor Zhang is named on most of the patents so far awarded and has claimed that his key inventive step, published in January 2013, was to show that Crispr-Cas9 works in mammalian cells, including human cells.

Jennifer Doudna is professor of chemistry and molecular cell biology at the University of California, Berkeley. She co-authored a key scientific paper published in the journal Science in August 2012 showing that Crispr-Cas9 has the potential to work as an incredibly efficient and effective gene-editing tool. Professor Doudna has been a leading figure in the group of scientists who have called for a wide-scale public debate on whether the technique should ever be used to change the human “germline” of sperm, eggs and embryos.

Emmanuelle Charpentier started her research in Paris before moving to the United States. She also worked in Sweden where she is credited with discovering the potential of the Cas9 enzyme to edit genes with the help of the Crispr system. One of her key studies was with Jennifer Doudna, and she was a co-author of the August 2012 paper in Science. She has since returned to Europe and is now based in Germany at the Helmholtz Centre for Infection Research.

Better than Crispr?

Scientists have discovered an even more powerful tool for editing the genome than Crispr-Cas9 thanks to a trawl through a library of biological enzymes used by bacteria to defend themselves from invading viruses.

Feng Zhang of the Broad Institute in Cambridge, Massachusetts, and his colleagues found that they could replace the Cas9 enzyme that has proved so good at snipping the DNA of genes with another bacterial enzyme called Cpf1.

Crispr, which stands for clustered, regularly-interspaced, short-palindromic repeats, is a complicated name for the relatively simple process of aligning a “guide” molecule, which is made to order to match a specific DNA sequence, against a precise position on the DNA double helix where editing it required.

The second element of the gene-editing technique is to cut both strands of the DNA double helix with the Cas9 enzyme used by some bacteria to attack invading viruses. But now Professor Zhang and his colleagues have found that they can replace Cas9 with a smaller and more effective enzyme called Cpf1, which they found in another bacterium.

The scientists, who reported the discovery last week in the journal Cell, said another advantage is that Cpf1 requires a guide molecule of RNA – a molecular cousin to DNA – that is only made of a single strand, whereas Cas9 needs two strands. This means the new gene-editing tool is even smaller than Crispr-Cas9, meaning that it should be easier to insert into the cells and tissues where the gene-editing is needed – for instance the muscles if treating muscular dystrophy with gene therapy.

A second advantage is that the Crispr-Cpf1 complex cuts DNA in a slightly different way to Crispr-Cas9. While Cas9 cuts both strands of the helix as precisely the same place, leaving “blunt ends”, the Crispr-Cpf1 complex cuts each strand at slightly different points, leaving short overhanging bits or “sticky ends” which scientists believe will make gene editing even more accurate.

“This has dramatic potential to advance genetic engineering…[it] shows that Cpf1 can be harnessed for human genome editing and has remarkable and powerful features. The Cpf1 system represents a new generation of genome editing technology,” said Eric Lander, director of the Broad Institute and one of the scientists who led the human genome project.