A couple of weeks ago, MilliporeSigma (a US subsidiary of Merck) announced that it had received a Notice of Allowance from the United States Patent and Trademark Office that its patent application related to its proxy-CRISPR technology would be issued. This will be the company’s first CRISPR-related patent granted in the US.
In this blog post I look at the CRISPR technology, the IP landscape surrounding it, and the potential application of this technology in Aotearoa.
What is CRISPR?
CRISPR (Clustered Regularly-Interspaced Short Palindromic Repeats) are part of an adaptive immune response within prokaryotic organisms (such as bacteria).
The name itself relates to the structure and pattern of the DNA sequence involved in this immune response:
- Short pieces of DNA code
- That read the same both backward and forwards (a palindrome)
- That are clustered together and repeated in a specific way within the chromosome of a bacterium or other prokaryote
The mechanism of the CRISPR prokaryote adaptive immune response is illustrated in the following figure.
From: Cavanagh P, Garrity A. (2014). “CRISPR / Cas9 – CRISPR: Prokaryotic Adaptive Immune System”. Retrieved February 22, 2019, from: http://sites.tufts.edu/crispr/crispr-background/adaptive-immune-system/ and https://sites.tufts.edu/crispr/files/2014/11/NaturalCRISPR2.png
- The bacterial cell is invaded by foreign DNA that may pose a threat
- The cell captures some of this foreign DNA and incorporates it into its own DNA within the CRISPR repeating sequence (exactly how this happens is not known, but this doesn’t matter when it comes to exploiting the next part of the CRISPR mechanism for genetic engineering purposes)
- The cell then makes an RNA copy of the CRISPR sequence that contains the foreign DNA
- This RNA joins with another RNA molecule within the cell, and:
- Together they combine with a protein called Cas9 to form an enzymatically active complex to target and attack the remaining invading DNA
- The RNA component of the complex contains complementary sequences to the invading DNA enabling it to specifically target and bind to the invader
- Cas9 then cuts, thus inactivating, the foreign invading DNA
Many tools used by molecular biologists exploit naturally occurring mechanisms like this to artificially manipulate DNA in the laboratory and the natural world. Scientists are able to use the components of the CRISPR mechanism to target, cut and modify regions of DNA from other organisms with a very high degree of specificity.
The CRISPR Patent Landscape
Since the early application of the CRISPR mechanism to the field of molecular biology and genetic engineering in 2012 / 2013, the technology has been further refined and understood. It is now an established part of the molecular biologist’s tool kit.
There are currently thought to be globally over 4,400 patent families (individual inventions) relating to the CRISPR technology, with nearly 200 new patent families being published each month. The majority currently originate from the USA, however filing in China is increasing rapidly.
A significant proportion of the new inventions are focussed on the Cas9 protein (which cuts the target DNA), the guide RNA (which targets the exact sequence to be cut), and the application of the technology within the field of diagnostics. However, patents are being sought for the technology in a wide range of fields from therapeutics to agriculture.
This field of technology and the IP surrounding it is rapidly evolving. The new MilliporeSigma / Merck patent, for example, develops the technology even further by enabling modification of parts of a genome that were previously difficult to access. Referred to as Proxy-CRISPR, it involves two CRISPR systems working together where one moves blocking chromatin proteins out of the way for the other system to access the specific, otherwise inaccessible locus for subsequent modification.
CRISPR in New Zealand
The Royal Society Te Apārangi has in recent years published a number of discussion and technical papers exploring the applications and impact of gene editing technologies in Aotearoa.
In particular, the papers have explored the use of the technologies in relation to New Zealand’s primary industries (such as agriculture and forestry) as well as the Predator Free 2050 programme (which is designed to rid Aotearoa of its most damaging introduced predators – rats, stoats and possums – by the year 2050).
For New Zealand’s primary industries, the following five gene editing scenarios are explored:
- Reducing Environmental Impact: using gene editing to sterilise trees (such as Douglas Fir) grown in forestry plantations, thus preventing the trees from “wilding”, i.e. establishing themselves outside of their intended plantation sites
- Responding to Insect Pests and Environmental Stress: beneficial fungi associated with rye grass, for example, can protect the grass from insect pests, but at the same time make it harmful to livestock – gene editing can to be used to remove the chemicals that harm stock, whilst retaining the chemicals that protect against pest damage
- Speeding Up Innovation: gene editing can be used to speed up the lifecycle of fruit trees (such as Apple) to reduce the time from sprouting to fruiting, thereby enabling faster development of economically important new cultivars and varieties
- Protecting Taonga (Culturally Valuable) Species: using gene editing to increase disease resistance in Mānuka, thereby protecting the Mānuka honey industry
- Providing New Human Health Benefits: gene editing can be used to remove the proteins in milk to which some people are allergic
For pest control in New Zealand, the use of gene editing associated with gene drive technology to reduce the fertility of the following three pest species are explored:
- Introduced, invasive wasps (the Common Wasp and the German Wasp)
- The Brushtail Possum
- Stoats and Rats (including the Common Rat, the Brown Rat and the Polynesian Rat)
Gene drives are a technology that use CRISPR for specifically modifying the genome of a target species to, for example, make the organism infertile.
Other mechanisms within cells (for example, damage repair mechanisms) are then exploited to artificially spread the modified gene through a population at a rate that is higher than average.
This “drives” the modified gene into more offspring than would occur by chance alone. In the case of an infertility gene, this process will ultimately lead to a population with such a high level of infertile members that it becomes unviable and dies out.
Gene editing has huge potential for applications in New Zealand, including improvements to agriculture & horticulture, protecting native species, and pest control.
From a primary industries perspective there is currently no global consensus on how to treat, manage and regulate genetically modified organisms arising from the gene-editing technologies discussed above. Some nations (e.g. the USA, Canada and Argentina) are relatively relaxed, not regulating against, for example, gene-edited plants provided no introduced DNA remains in the final plant, whilst other (e.g. the European Union) treat such plants as they would any other genetically modified organism. In Australia and China, a regulatory policy has yet to be decided.
For a country heavily dependent upon primary exports, this raises some challenges in deciding which technologies, if any, to pursue.
New Zealand itself currently adopts a relatively cautious approach and regulates all gene editing as a genetic modification procedure. The government defends this posture because of the country’s significant export market and the recognised need to be alert to both market perceptions as well as the supporting science. In order to maintain a globally competitive position, awareness of the position of major international partners is essential, and a global consensus would greatly assist also.
From a pest control perspective, this is still new technology, relatively untested in the field and will require appreciable additional research, and public awareness campaigns and consultation if it is to be successfully implemented.
Public perception of genetic modification may well prove also to be a major factor in determining the extent of the application of this technology in New Zealand. There is a need for better communication and education to ensure an informed debate is held.
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