When scientists debate whether some new technology will one day allow them to create flying pigs, the world rarely listens. Yet since CRISPR has been around, it has become a serious debate, and one with important consequences for the extent to which we can manipulate the "code of life" (DNA).
CRISPR is a revolutionary gene-editing technology, mainly praised for its potential to prevent or treat serious human diseases such as cancer or HIV. Its scientific and commercial appeal has sparked fierce patent litigation in the US – essentially a fight over ownership of editorial control over all of life's genome. A ruling from the US Court of Appeals for the Federal Circuit last month might draw it to a close (for now).
Genetic engineering, the manipulation of an organism's DNA, has been around for decades. CRISPR is a technology for gene editing, which is a particularly precise form of genetic engineering. To understand how CRISPR works and how revolutionary it is, let us recount the history of its discovery. In the 1980s, scientists studying the DNA of E. coli bacteria found five identical, consecutive sequences of code, separated by very short random sequences.
The fact that nature, at this low level of organism, was clustering identical sequences of DNA, had to mean something. Eugene Koonin, a Russian-American biologist, hypothesised in 2005 that this system amounts to a defence mechanism whereby the bacteria cut out sequences of DNA from viruses that attack them and store them for later recognition. The next time the virus attacks, the bacteria send out proteins that crawl their DNA carrying a copy of the virus DNA's sequence, which acts as a 'mugshot' allowing them to identify bits of virus DNA. Once identified, they cut them out. In essence, CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a bacterium's antiviral system.
In 2012, a team of biochemists at UC Berkeley (UC), led by Jennifer Doudna and Emmanuelle Charpentier, managed to turn this intriguing system of virus defence into an offensive gene editing one. By replacing the 'mugshot' of virus DNA with one of some disease-causing gene, they were able to faultlessly target and cut out the problematic gene. The team then found it relatively simple to replace it with a new good gene: they introduced it in the vicinity of the gap, after which it was picked up by repair molecules and inserted in the empty spot.
The precision of this technology is what sets it apart from all previous methods of gene editing, which rely on giving unreliable directions to a gene editor. These directions are rarely followed strictly, producing low rates of success, very high costs and long timeframes. In short, CRISPR is countless times more accurate, cheaper, and quicker, and can be used for virtually any type of editing needs. In the words of its creator, CRISPR is "a democratizing technology. It just opens the door to anybody who has basic skills in molecular biology and wants to do some genome editing".
Such a simple and cheap way to edit the code of life has gotten eugenicists excited, raised fears of Jurassic Park becoming reality, and made designer babies 100% possible. On the bright side, CRISPR may help cure serious genetic diseases such as cystic fibrosis, by editing out the responsible gene. Research on other diseases might also benefit as CRISPR can be used to study the role of certain genes in the expression of those diseases (a biomarker for Alzheimer's disease was found using CRISPR).
However until now, only scientists in China were allowed to trial CRISPR technology in living humans. In 2016, they used CRISPR to edit out a certain expressed gene in people suffering from lung cancer. A considerable obstacle to human trials in the US was cleared a few days ago when the FDA lifted its hold on clinical trials for the treatment of sickle cell disease. In Europe, a Phase 1/2 clinical study is set to start by the end of the year, potentially leading the way to human trials. Many more applications of CRISPR are being considered, from making crops insect-resistant (eradicate the need for pesticides), to altering the genome of mosquitoes so that they cannot carry malaria.
The scientific potential of CRISPR is only bound by the limits of imagination – and so is its commercial potential, which has made it subject to hot patent litigation in the US. Doudna and Charpentier's team at UC Berkeley filed patents in 2012 on the use of CRISPR-Cas9 (the protein they reengineered to target DNA sequences) to edit short snippets of DNA in small, non-cellular organisms, like bacteria.
At the time, they expressed doubts about the ability to use CRISPR-Cas9 to edit the genomes of eukaryotic cells (those of plants and animals). In 2014, while their patents were pending, a team at the Broad Institute of MIT and Harvard (Broad) filed a patent on the use of CRISPR-Cas9 on more complex cells such as those of mammals, which was approved in 2017. The US Patent and Trademark Office (USPTO) decided in February 2017 that UC's patent did not render obvious Broad's claims to the use of CRISPR-Cas9 in eukaryotes – the use of CRISPR-Cas9 in a non-cellular experiment and its use in living creatures was different enough to deserve two separate patents. The USPTO's decision was upheld on 10 September 2018 by the US Court of Appeals for the Federal Circuit, likely putting an end to the litigation.
The significance of this decision is difficult to gauge, given the speedy pace of research in the field. The coexistence of two significant patents on CRISPR-Cas9, one for the use on cell-free systems and one for the use on eukaryotes, might complicate things for small biotech companies who may have to obtain licenses from both UC and Broad in order to exploit the technology. One effect of the decision was that the stock of Broad's surrogate company (Editas) went up 36% after the USPTO decision in 2017.
The picture is slightly less rosy for Broad in Europe at the moment, where the European Patent Office Opposition Division found its patent invalid due to a technical error in the application. One of the inventors figuring on the US filings was not included in the European application, preventing Broad from claiming the priority date of the earlier US patents. This decision is being appealed. However, the many follow-on patents that Broad has filed, such as alternatives to the Cas9 enzyme used in early versions of CRISPR, are still intact.
Broad has been in discussions to create a worldwide CRISPR-Cas9 licensing pool, "a one-stop shop for commercial users to license CRISPR patents without needing to navigate a complex patent and licensing landscape". At the moment, commercial groups who wish to use CRISPR may need to apply for licenses from many inventors or institutions: more than 60 CRISPR-related patents have been granted in the US, and 20 have been issued in Europe.
A worldwide licensing pool might streamline the process and reduce the cost of commercialisation. CRISPR is currently licensed through exclusive rights for all human therapeutics across all human genes, while uses such as academic research or agricultural applications are licensed on a nonexclusive basis. While the recent US decision complicates the CRISPR patent landscape, it does not spell doom for the thousands of scientists eager to let their imagination flow from the prospects that CRISPR opens.