by Nessa Carey
Although the results were startling, the approach used was fairly blunt. Gene editing was employed to remove quite large areas of the genome, which usually carry critical epigenetic information. A lot of the work the researchers carried out involved finding the regions where such wholesale loss of genetic and epigenetic information was tolerable. A much more elegant approach would be to use the new gene editing technologies to alter the epigenetic information, while leaving the native DNA sequence intact. Although still in its infancy, this field is already making progress and in the next few years we will probably see substantial improvements to our understanding of the precise impact of a whole range of epigenetic modifications on the genome, and its interaction with the environment.10
This doesn’t mean that we are likely to see a similar use of gene editing happening in human IVF, to create babies from single-sex couples. Although the gene editing stage was relatively straightforward, the rest of the interventions were incredibly complex and required very specialised cell populations. The survival rate of the embryos was also incredibly low. The safety, efficacy and ethical barriers to moving this to humans are many, varied and unlikely to be tackled in the foreseeable future.
Notes
1. Trible W., Olivos-Cisneros L., McKenzie S.K., Saragosti J., Chang N.C., Matthews B.J., Oxley P.R., Kronauer D.J.C. ‘orco Mutagenesis Causes Loss of Antennal Lobe Glomeruli and Impaired Social Behavior in Ants’. Cell (10 August 2017); 170(4): 727–735.
2. Zhang, L., Mazo-Vargas, A., Reed, R.D. ‘Single master regulatory gene coordinates the evolution and development of butterfly color and iridescence’. Proc. Natl. Acad. Sci. USA (3 October 2017); 114(40): 10707–10712.
3. Mazo-Vargas, A., Concha, C., Livraghi, L., Massardo, D., Wallbank, R.W.R., Zhang, L., Papador, J.D., Martinez-Najera, D., Jiggins, C.D., Kronforst, M.R., Breuker, C.J., Reed, R.D., Patel, N.H., McMillan, W.O., Martin, A. ‘Macroevolutionary shifts of WntA function potentiate butterfly wing-pattern diversity’. Proc. Natl. Acad. Sci. USA (3 October 2017); 114(40): 10701–10706.
4. Nicholas Wade. ‘Genes colour a butterfly’s wings. Now scientists want to do it themselves’. The New York Times (18 September 2017).
5. Nicholas Wade. ‘Genes colour a butterfly’s wings. Now scientists want to do it themselves’. The New York Times (18 September 2017).
6. Fei, J.F., Schuez, M., Knapp, D., Taniguchi, Y., Drechsel, D.N., Tanaka, E.M. ‘Efficient gene knockin in axolotl and its use to test the role of satellite cells in limb regeneration’. Proc. Natl. Acad. Sci. USA (21 November 2017); 114(47): 12501–12506.
7. Fei, J.F., Knapp, D., Schuez, M., Murawala, P., Zou, Y., Pal Singh, S., Drechsel, D., Tanaka, E.M. ‘Tissue- and time-directed electroporation of CAS9 protein-gRNA complexes in vivo yields efficient multigene knockout for studying gene function in regeneration’. NPJ Regen. Med. (9 June 2016); 1: 16002.
8. For a full description of Azim Surani’s work, and more detail on these epigenetic modifications, I egregiously recommend my own book, The Epigenetics Revolution, first published in 2011 by Icon and still going strong. I have no shame.
9. Li, Z.K., Wang, L.Y., Wang, L.B., Feng, G.H., Yuan, X.W., Liu, C., Xu, K., Li, Y.H., Wan, H.F., Zhang, Y., Li, Y.F., Li, X., Li, W., Zhou, Q., Hu, B.Y. ‘Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions’. Cell Stem Cell (9 October 2018); pii: S1934–5909(18): 30441–7.
10. Liu, X.S., Wu, H., Ji, X., Stelzer, Y., Wu, X., Czauderna, S., Shu, J., Dadon, D., Young, R.A., Jaenisch, R. ‘Editing DNA Methylation in the Mammalian Genome’. Cell (22 September 2016); 167(1): 233–247. e17.
* Lizards can’t regenerate their limbs but presumably The Smiling Salamander didn’t sound sufficiently menacing as a super-villain.
10
FAME AND FORTUNE
Governments invest funding in scientific research for a variety of reasons. One perfectly valid one is that good science is one of the great cultural achievements of humanity, just as much as the paintings of Raphael or the novels of Jane Austen. But governments also invest because they expect a return on their investment. They hope that their gamble will pay dividends in terms of positive impacts. These impacts can take various forms – greater well-being of their citizens through public health initiatives; increased global stability thanks to improved security of food supplies; a slowdown in climate change through enhanced technologies for using renewable sources of energy are a few large-scale examples.
But governments also hope that their investments in science bear fruit in more overtly and directly financial ways. They like to see that some of the work they fund leads directly to commercial outcomes, generating cash for the academic institutions, and ideally leading to the creation of companies that hire highly skilled individuals and stimulate growth and the economy.
It can be very difficult to predict which investments in research will lead to direct financial benefit. One of the most successful academic centres in the world for the generation of a financial return on investments in research is Stanford University in California. One of the business mechanisms they use for generating commercial income is to out-license the intellectual property created by their researchers. This basically means that companies that take out a licence to a particular technology pay Stanford a fee if they manage to make money by using the invention. But the reality is that most of the out-licensed intellectual property doesn’t become the basis of a successful product. About 70% of the licences that Stanford grants generate little or no income. It’s basically very difficult to predict the winners in the new technology sweepstake.
But just occasionally there’s a new technology that is clearly a game-changer, and with enormous economic potential. Gene editing is one such innovation. Its applications are incredibly widespread, from basic research to the creation of valuable new plant and animal strains, and it’s so easy to use. It was inevitable that gene editing would be the subject of intense commercial interest. Just a few years after its creation it’s already making a lot of money for some companies. Unfortunately, these companies are law firms.
I’ll see you in court
A simple search of a patent database shows at least two thousand documents referring to gene editing. These cover a wide range of modifications to, and improvements of, the original technology. There are two patent application families that are considered the most important, however, and these are the ones filed right at the start, when researchers first demonstrated how to use the technology to change any gene sequence.
A quick reminder of the key players is timely here. In June 2012 Jennifer Doudna and Emmanuelle Charpentier published their work, using a hybrid guide molecule and showing that the gene editing system they had developed worked in test tubes, not just in bacteria. Their employers at the University of California, Berkeley and the University of Vienna filed the patent application to protect this in May 2012. In February 2013 Feng Zhang from the Broad Institute* in Cambridge, Massachusetts published his paper in which the gene editing took place inside the nucleus of cells. His employer filed a patent application in December 2012.
This might all seem straightforward, with Doudna and Charpentier being the first to publish and the first to file patent applications. Patenting is basically a first-past-the-post system, where the winner takes it all.
If only it were that simple and clean.
The Broad Institute paid to have its application fast-tracked by the US Patent Office and its patent was granted in April 2014. Many observers were surprised that the Patent Office agreed to rule on the Broad’s application when the earlier one from UC Berkeley and University of Vienna was still going through the system. It was fairly obvious that the two applications would be entangled. But rule they did.
Doudna and Charpentier’s universities cried foul, although not about the accelerated review of their rival’s application. They based their objections to the granting of the Broad patent around the issue of ‘obviousness’. Let’s imagine you created
a new type of lock. You filed a patent application, and this included ways of designing the lock so that it would work in house doors, apartment doors, stable doors and barn doors. Let’s say someone else then tweaked your invention, modifying it very slightly, and filed a patent for the use of their lock in shed doors. The patent authorities would probably not grant the second patent, arguing that the minor amendment and slightly altered use were very obvious extensions of the original invention. For anyone ‘skilled in the art’ (in this case of creating and installing locks) this would have been such an obvious application of the original invention that you shouldn’t be rewarded for making the change.
This is essentially the approach taken by UC Berkeley and the University of Vienna. Their position was that Doudna and Charpentier had worked out all the key steps, and Feng Zhang just applied these and extended them a bit, but didn’t do anything particularly smart or inventive. The US Patent Trial and Appeal Board disagreed. In 2017, it ruled that Feng Zhang’s work was sufficiently different and inventive that it was not covered by, or implied in, the original patent application from Doudna and Charpentier.1 In September 2018 the US Court of Appeal upheld the ruling.2
This is a major setback for UC Berkeley and the University of Vienna. The patent from the Broad Institute based on Feng Zhang’s work covers the use of gene editing in any cell with a nucleus. This includes all plants and animals and is where the real monetary value lies in the technology.
But the complications didn’t end with this ruling. The European patent authorities have ruled against the Broad Institute, partly based on a bizarre spat about inventorship. When the Broad filed its original patent application, one of the co-inventors was a collaborator from the University of Rochester, Luciano Marraffini. He was dropped from subsequent filings and this had two consequences. One was that the University of Rochester filed its own patent application, possibly as a way of putting pressure onto the Broad Institute to share the financial upside from the patent (the two organisations eventually settled their dispute out of court). The other was that the European Patent Office took a dim view of the change in inventors, deciding that this meant the original application date was no longer valid.3 By the time the Broad Institute filed its subsequent applications, lots of the underlying research had already been published. Under European law, you can’t get a patent for something which is already in the public domain.
So, now we have a tangled situation where the owners of the incredibly valuable intellectual property underpinning one of the most transformational developments in biology are different, depending on where you are in the world. This is going to create a very confused and confusing commercial picture for quite some time.
Gene editing was only invented in 2012, so how can we be so confident that it’s commercially valuable? One clear sign is the amount of money that the key parties have spent fighting over the foundational patents, which is already in the tens of millions of dollars range. Another is the billion dollars or so that have been invested into the main companies working to develop gene editing commercially.
The fortune
The biggest names in gene editing are undoubtedly Jennifer Doudna, Emmanuelle Charpentier and Feng Zhang. The three of them discussed setting up companies together in various configurations, but none of these combinations worked long-term. The three scientists have been commendably discreet on the reasons why this didn’t work out. Each of them is now significantly involved in gene editing companies they themselves helped to found. These three companies are the biggest ones in the gene editing field. Jennifer Doudna is a co-founder of Caribou Biosciences, headquartered in Berkeley, California. Emmanuelle Charpentier is the co‑founder of CRISPR Therapeutics whose main research site is in Cambridge, Massachusetts, but with its corporate headquarters in Switzerland. Feng Zhang is a founding scientist of Editas Medicine, also based in Cambridge, Massachusetts.
These companies are well funded and valuable. Caribou Biosciences remains in the ownership of private investors. The other two companies are both listed on the US Stock Exchange. Editas Medicine is currently valued at $1.2 billion and CRISPR Therapeutics at $2.6 billion. These numbers are rather startling when you consider that none of these companies has actually sold any products, except for research reagents.
These companies don’t just have the cachet of association with the fabulous leading scientists in the gene editing field. They also have access to the intellectual property they generated, including the discoveries covered in the contentious patents (and many follow-on patent applications as well). Editas Medicine holds the licences to the key patents filed by the Broad Institute and it is Editas Medicine who have been paying the bill for the legal costs of the Broad’s patent fights. So far this has amounted to nearly $15 million.4 Caribou Biosciences, the company founded by Jennifer Doudna, has reimbursed the University of California, Berkeley for the $5 million or so they have spent on the legal fisticuffs.
The litigation is so costly because the stakes are so high. Potentially every company in the world that wants to use gene editing to create commercial products may have to pay royalties to the owners of the foundational patents. These royalties will probably be based on the ultimate sales of the products and could be billions of dollars globally. The three leading companies in the space also need to defend their own rights to create products without paying royalties to other companies. So not only do they need to defend their current position, they also need to stay ahead of their opposition with access to new developments.
An example of this is a recent deal between Editas Medicine and the Broad Institute. The company has committed up to $125 million in research funding for the Broad, for which it will get first rights of refusal on new inventions in gene editing.5 $125 million is a lot of money to fund scientists to do work you can’t control, with no guarantee of what they will create. We can be certain that this won’t be the last deal like this that we’ll see.
The fame
Patents are legal instruments covered by swathes of legislation, but they still rely on human interpretation, for example to define whether a new claim really represents a genuinely inventive creation, or just more of the same. But there are certain aspects that are fairly straightforward with patents. It’s easy to tell who filed a patent first and in most jurisdictions this is what counts in terms of whose intellectual property is protected. If two independent inventors submit a patent application for very similar inventions, the protection will be given to the one who filed first, even if just by a day. This can be incredibly important in terms of who makes money from the invention.
Money isn’t the only thing that matters, though. No one is suggesting scientists don’t like money, but it’s not usually their main motivation, probably because so few of them actually make much from their work, beyond their salaries. Much more important are the satisfaction of making new discoveries, and the acknowledgement of their peers. When a field moves very fast, it can be hard for observers to know the exact sequence of discoveries, and whose work led on from whose. Gene editing is no exception. The field started quite slowly with the basic science findings about bacterial defence systems but picked up speed rapidly when researchers with an interest in altering genomes woke up to the possibilities in front of them.
Clarifying the narrative around gene editing was probably the rationale behind a decision at the journal Cell to commission a review of the history of this transformational technology. Cell is the world’s leading journal in biological sciences. It mostly publishes highly innovative and important new research but it also sometimes prints major reviews. No one in the scientific community was surprised that Cell took it upon itself to publish an extensive history of the gene editing story. No one was surprised that they wanted it to be written by a high-profile scientist with a great writing style. But everyone was surprised that the person who wrote the review for Cell was the President and Founding Director of the Broad Institute. Yes, that Broad Institute, the one at the centre of the gen
e editing patent disputes.
Eric Lander, the individual involved, has a stellar scientific record in the field of genetics, and he writes in a beautifully accessible style. But there was no way that he could come out of his review, entitled ‘The Heroes of CRISPR’,6 unscathed. One observer compared him to a character from Greek tragedy, commenting that: ‘The only person that could hurt him was himself. He was invulnerable to anybody else’s sword.’ This statement was made by Professor George Church, another gene editing pioneer and a colleague of Lander at the Broad.7
Disquiet about Lander’s article was widespread. It has generally been perceived as an attempt to play down the role of Doudna and Charpentier, and to put Feng Zhang centre-stage in the development of the technology. As George Church commented: ‘Normally I’m not so nitpicky about all these errors. But as soon as I saw that they [Lander and Cell] were not giving the young people, the people who actually did the work, and Jennifer and Emmanuelle, adequate credit, I just said, “No, I have to correct what I know to be false.”’8
Lander spends a lot of time on the work of Virginijus Šikšnys from the University of Vilnius, who was working on the same types of approaches as Doudna and Charpentier. Šikšnys submitted his work for publication in April 2012, but it was rejected by Cell and eventually published in a shorter form in another journal in September of the same year. Doudna and Charpentier submitted their paper to Science (another world-leading journal) on 8 June 2012 and it was published on 28 June. A reader might infer from Lander’s review that Doudna and Charpentier gained an advantage by being better at gaming the publication system. But we have no idea why Šikšnys’s original manuscript was rejected. It’s possible that the Science paper was simply more convincing.
