The $10 billion market
What are the inventors of gene editing fighting for
Alexey Aleksenko, Forbes, 06.03.2019
The first articles about gene editing using CRISPR technology appeared in 2012. Just six years later, Chinese biologist He Jiankui used a method – reputedly in violation of ethical norms – to edit the human genome. Over the years, the use of CRISPR in medicine and biotechnology has been the subject of a patent dispute between two research teams: the University of California at Berkeley, where Jennifer Dudna, one of the discoverers of the technology, works, and the Broad Institute in Massachusetts, which was the first to announce the possibility of gene editing in mammalian cells. In 2018, there was a new turn in history: the CRISPR technique was successfully used for tasks not related to gene modification. It turned out that the method has a huge potential for medical diagnostics: two articles on this topic were published almost simultaneously. Biologists from California and Massachusetts became the main rivals again.
How CRISPR helps to find the virus
The CRISPR bacterial immunity system came to the attention of researchers back in the 1980s. The possibilities of its practical application are based on the fact that the system is able to find a certain DNA sequence with great accuracy (in the case of bacteria, this is the chromosome sequence of a bacterial virus attacking a cell). In combination with the Cas9 protein, the system allows you to make a point break at a given point in the genome, which is what the classical gene editing system described in 2012 is based on.
However, the ability to accurately find the specified genetic sequence in itself is of great value – in particular, for medical diagnostics. Viruses attacking the human body contain not only unique viral proteins, but also unique sequences of viral genes. Classical methods of immunodiagnostics are based on the recognition of proteins using antibodies. In recent decades, diagnosis using polymerase chain reaction (PCR) has become widespread, the essence of which is to search for genetic markers of an infectious agent with a known sequence of nucleotides. The CRISPR diagnostic method is also based on the recognition of genetic markers, but differs from PCR diagnostics in its speed, simplicity and comparative cheapness.
A variant of the method proposed by Feng Zhang's group from the Broad Institute in Massachusetts is based on the use of the Cas13 protein. It differs from Cas9 in that after recognizing its target, instead of a single incision in the specified location, it begins to destroy all RNA molecules in its reach. For diagnostics, RNA molecules are used, to one end of which a dye molecule is attached, and to the other – a substance that blocks coloring. When the system recognizes a virus corresponding to a given sample, the protein begins to destroy RNA molecules, so that the dye is released "from under the yoke" of the inhibitor. As a result, the reaction mixture is colored. Such a reaction can be carried out on a paper strip, somewhat similar to a classic pregnancy test. The method is called SHERLOCK.
The method proposed by Jennifer Dudna's group is very similar. The test system was named DETECTR and it is based on the Cas12a protein, which acts in general the same way as Cas13, but destroys not RNA, but DNA.
Both methods have similar – and very high – sensitivity (of the order of nucleic acid attomoles). SHERLOCK's effectiveness has been demonstrated in the diagnosis of dengue, Zika, Ebola viruses, and most recently during the epidemic that spread in Nigeria, Lassa fever. The DETECTR system was used for the differential diagnosis of two types of papillomavirus associated with cervical and rectal cancer.
The prospects of using new diagnostic systems in developing countries are particularly interesting. Diagnostic kits are relatively cheap and, most importantly, the analysis does not critically depend on an uninterrupted supply of electricity. This method is strikingly different from PCR, where even a minute voltage drop can spoil the result. The analysis takes only a couple of hours, compared to about 6 hours in the case of PCR diagnostics.
Who was the first
The issues of scientific priority in the field of CRISPR technology are practically not controversial. The priority is shared by three researchers: Jennifer Dudna from the University of California at Berkeley, Emmanuel Charpentier from Sweden and Virginius Shikshnis from Vilnius University. The first article in 2012 was submitted to the editorial office by Shikshnis and his colleagues, but it was rejected without review. As a result, an article by Dudna and Charpentier was published first, and only a month later an article by Lithuanian biologists appeared.
The priority of the Shikshnis group was finally recognized in 2018, when all three discoverers were awarded the Kavli Prize (the Norwegian equivalent of the Nobel Prize). In 2015, Dudna and Charpentier became laureates of the Brealthrough Prize, established by Yuri Milner, but then Virginius Shikshnis was not among the laureates.
Feng Zhang from the Broad Institute (MIT) did not claim scientific priority, but it was his group that became the main actor in the patent dispute that began back in 2012. Their patent application explicitly stated the possibility of using the method for editing the mammalian genome. There was no such reservation in Dudna's application, submitted a month earlier. In the subsequent litigation, which ended in September 2018 with the victory of researchers from Massachusetts, the concept of "non-obviousness" became a stumbling block for lawyers: lawyers at the University of Berkeley insisted that the use of the technology on mammals was "obvious," and the Massachusetts side disputed this, in which it achieved success. Emmanuelle Charpentier stated that she did not intend to interfere in the patent dispute of her American colleagues, and kept her word.
It should be noted that the Cas12a protein used by Dudna's group in the DETECTR system was patented by Feng Zhang back in 2015. However, the application did not mention that it could be used in diagnostic systems. Thus, the concept of "non-obviousness" may this time become the weapon of the other side in the dispute. Meanwhile, California researchers are working on improving the DETECTR system using Cas14 and Cas X proteins. It is possible that patent disagreements between the two groups of researchers will soon reach a new stage. Both groups are working on multichannel diagnostic systems, for which it is desirable to use as many different CRISPR-associated proteins as possible, and it is unlikely that it will be possible to "divide honestly" the various elements of the bacterial immunity system between different groups.
Patents and progress
Among the co–founders of the first startup for commercial use of CRISPR – Editas Medicine - were both Feng Zhang and Jennifer Dudna. However, after the patent dispute began, Dudna left the startup and founded her own company, Intellia Therapeutics. Currently, the intellectual property of the Dudna Group has been transferred to the companies Intellia Therapeutics, CRISPR Therapeutics and Caribou Biosciences: the latter owns 7 US patents on CRISPR technologies. The Broad Institute holds 13 patents, and another 14 belong to Harvard. The holder of one US patent is also Vilnius University. In total, as of fall 2017, 80 patents for CRISPR technologies were registered in the United States, and more than 200 in the world. A detailed analysis of the situation with the licensing of developments in the field of CRISPR was published in Science two years ago, but since then there have been changes in it.
The rights to the SHERLOCK diagnostic system belong to Editas Medicine. In California, to develop DETECTR diagnostic systems, Jennifer Dudna founded a separate company, Mammoth, to which the rights to the technology were transferred.
In 2017, MPEG LA (Colorado) proposed to patent holders in the field of CRISPR to create a common patent pool that would facilitate licensing for biotech startups. The Massachusetts researchers supported the initiative and have already provided 22 of their own patents, both approved and pending. Nevertheless, the process of intellectual property integration is not going too fast, and from a legal point of view, the area of licensing CRISPR technologies remains difficult to navigate.
In 2018, the global market for CRISPR technologies was estimated at about half a billion dollars, but growth to $3 billion was expected over the next five years. According to other estimates, the market will reach $10 billion by 2027. Anton Hopka, head of the Atem Capital investment fund, notes that such estimates and forecasts should be treated with caution: "CRISPR technology is quite young and is not yet used on an industrial scale. The main application of the technology is currently at the research stage."
According to Hopka, investors' interest in the industry is quite high, despite a number of factors that would normally make investments unacceptably risky: "These are not only extremely difficult patent disputes, but also constant problems with the stability of technology, the lack of an array of data on the use of technology in humans, non-obvious regulatory aspects."
According to Konstantin Severinov, a professor at Skoltech and Rutgers University (New Jersey), a leading Russian expert on CRISPR technologies, he is not aware of Russian startups focused on the commercial use of this technology in biomedicine.
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