CRISPR: Biotech breakthrough, IP battle and ethics questions of the century

The science of slicing and splicing

Doudna and Charpentier’s tool, the Clustered Regular Interspaced Short Palindromic  Repeats/CRISPR associated protein 9 tool – CRISPR/Cas9 for short – has been described as a “molecular scalpel for genomes” and is touted as the biggest life sciences discovery in 100 years. A star-studded award ceremony was held in honor of its discoverers, and the prize money they won was dished out by famous tech billionaires, including Mark Zuckerberg.

But why all this fuss? Because, using CRISPR/Cas, it is possible to precisely modify, cut out, or replace a gene sequence within a genome; a.k.a. quick and easy genetic modification. It represents an unprecedented leap forward in gene-splicing technology, which has historically relied upon the slow, inefficient introduction of mutations into animal genomes by specialized labs. CRISPR/Cas is driven by specially-engineered ‘guide-RNA’ used to target sequences in precise locations on a genome.

Initially, Doudna and Charpentier demonstrated the successful slicing and replacement of gene sequences in bacterial cells, which are much simpler than the complex cells — or eukaryotic cells — of higher organisms. However, they later reported success in editing human genes ... in the very same month that the team of Feng Zhang of the Broad Institute, Inc and MIT separately achieved the same success with the technology. Cue the patent battle!

The discovery that drives CRISPR/Cas is no secret, and Doudna and Charpentier have been fully credited with its development. Even so, the intellectual property rights to the technology — which have the potential to generate huge amounts of cash for their owner — are under dispute because it was used by two separate teams to achieve the same milestone: successful edits of eukaryotic cells. So, who did it first, and does it matter? We’ll get to those questions in a bit.

It's no secret, but it is safe?

CRISPR/Cas is a powerful gene engineering tool that could have widespread impacts upon all areas of life sciences. Even though it is well-understood by scientists, the technology isn’t perfect, even when used under ideal circumstances. Although precise, the guide-RNA used in CRISPR/Cas isn’t 100% accurate, potentially leading to unintended changes to the genome, called ‘off-target’ effects.

Off-target effects could be unnoticeable, or they could have substantial negative impacts on the organism being mutated. There are several ways to seriously limit the chance of off-target effects and avoid them, including the use of software tools to make sure that the design of the guide-RNA is as specific as possible, and the limitation and modification of the RNA and Cas9 proteins being used to identify and slice gene sequences.

With CRISPR/Cas technology you can also create efficient ‘gene drives’. Gene drives can be used to push – even potentially harmful – genetic modifications into wild populations of an organism. Gene drives should be designed and used very carefully. Also avoid the creation of a gene drive by accident. When you use non-integrating Cas9 constructs or purified Cas9 proteins and sgRNA you will not create a gene drive by accident.

The clash for cash: intellectual property and tech transfer

Despite the fact that Doudna and Charpentier applied for a patent on the basic CRISPR/Cas technology 6 months before Zhang, he was awarded the first US granted patent. How? His backers were able to get him prioritized examination under a specific US patent program. It’s a close fight because of those eukaryotic cells, which Zhang targets as specific provisions of his patent, and which is also where the money is. But do these specific applications fall under the broader umbrella of Doudna and Charpentier’s US patent application, which was submitted before Zhang’s, but also before the ‘first-inventor-to-file’ system was activated in the US on 16 March 2013? It’s still a heated debate.

Jan Demolder, VIB’s senior IP Manager, feels that diverse players in the biotech community should have access to CRISPR technology. “It shouldn’t just belong to a single party. Non-exclusive licenses should be granted to parties in a range of different disciplines — agriculture, healthcare and industrial biotechnology, for example — for maximum societal benefit,” he explains. “CRISPR/Cas is one of the biggest, brightest stars in recombinant DNA tech,” continues Jan. “It’s generating the publication of hundreds of scientific papers. Since VIB is an academic institution, we can rely on the research exemption to use this technology as long as we stick with academic research without commercializing our findings.”

When asked how this USpatent infringement situation will affect businesses, Jan replies: “With two parties squabbling over the rights, the legal situation is still up in the air for companies that want to invest in CRISPR/Cas-based applications.” In other words, the longer the battle draws out, the more money the duelers will spend defending their cases, and the longer companies will have to wait before having legal certainty. In the meantime we see many new players developing improvements of the CRISPR-technology and also on the development of patent design around strategies.

CRISPR/CAS stires up and revives societal debates 
CRISPR/Cas presents a revolution in scientific research comparable to the introduction of PCR in the second half of the 1980s. But where PCR was a mere detection tool, CRISPR/Cas is an engineering tool. It’s a tool that generates great enthusiasm among scientists, but it also provokes societal debate on different fronts.

CRISPR/Cas and possibilities to engineer the human genome

The possibilities created by CRISPR/Cas also once again stir up the debate on engineering of the human genome. For classical gene therapeutic approaches there is a worldwide agreement not to engage in germline gene therapy. But the ease and precision brought by CRISPR/Cas puts new pressure on the debate. Chinese researchers have already applied the technology to introduce a mutation that renders humans resistant to HIV infection into a defective embryo left over from an in vitro fertilization. Most researchers however are very careful to consider the use of CRISPR/Cas for human genome engineering. In most cases the use of CRISPR/Cas is not necessary because a certain disease causing genetic defect can be prevented from being passed on to the next generation by applying pre-implantation genetic diagnosis. There are however certain cases where pre-implantation diagnosis or classical somatic gene therapy cannot help, and there is debate at the highest level on the ethics of the use of CRISPR/Cas in such cases.

CRISPR/Cas and the creation of ‘hidden GMOs’

Genetically modified organisms (GMOs) are the subject of great controversy. NGOs have been campaigning against GMOs for many years with success. For them, GMOs represent a technological evil dominated by multinational corporations that wish to take over agriculture and food production. They see CRISPR/Cas as yet another technology that is used to engineer the genetic make-up of organisms in a highly technological fashion. To them, these organisms are GMOs by definition and should be strictly regulated. Where scientists point to the precision of the technology, they point to uncertainties and possible off-target effects. The jury is still out as to whether the use of CRISPR/Cas leads to the formation of organisms subject to the requirements of GMO legislation. If the opinion of the European Commission, which is expected over the course of 2016, states that they are not, NGOs are likely to challenge this at the European Court of Justice. But whether it is to be considered a GMO or not, NGOs will in any case continue to perceive the use of CRISPR/Cas as unnatural, even though in most cases the edits generated can or do occur in nature, and cannot be distinguished technically from natural mutations.