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January 02, 2015

Gene Editing Will Change Everything—Just Not All at One Time

Transformative technology is still in its infancy but great things are expected in human health and industrial and agbio markets.

Gene Editing Will Change Everything—Just Not All at One Time

Gene editing holds the promise of transforming the way R&D is conducted across major sectors of the global life science economy. [© Kirsty Pargeter/Fotolia.com]

  • From the discovery in the late 1980s by researchers at Osaka University of strange repeat DNA sequences sitting beside a gene in a common bacterium, to the frenzied deals and financings over CRISPR technology today, gene editing has taken firm hold in the worlds of basic and applied life science. In fact, the variety of gene-editing technologies goes way beyond CRISPR, and its commercial applications go beyond human therapeutics to encompass agriculture, both plants and animals, and a broad array of high-margin industrial products. In short, gene editing holds the promise of transforming the way R&D is conducted and products developed across major sectors of the global life science economy.

    Gene editing broadly refers to a suite of methods that use site-specific endonucleases to first target a double-stranded break in the genome and then to repair that gene by disrupting it or by rewriting its sequence. Over the course of the past few decades, the technology has progressed through the use of meganucleases (MEGAs), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats (CRISPRs). Each specific iteration of the technology has been easier to design and has brought gains in speed and ease-of-use.

    Thus far, Sangamo Biosciences is the only company to have applied one of these technologies —ZFNs—to the development of clinical-stage human therapeutics. Other companies such as the start-ups CRISPR Therapeutics and Editas Medicine have focused on CRISPR and have attracted eye-opening investments by elite early-stage VCs. In December, Editas completed multiple licensing deals on the same day for the gene-editing technologies TALEN and CRISPR/Cas9 (Cas9 refers to the protein that binds to RNA molecules which guide it to a specific location on the genome where it triggers a double-stranded break).

    And recently, big pharma has entered the field. Last June, Pfizer inked a deal with Paris-based Cellectis to harness the biotech’s gene-editing capabilities to the development of CART-T (chimeric antigen receptor T-cell) anticancer immunotherapies. 

    Nonetheless, CRISPR, whose relative ease of use has made it the research tool of choice for achieving specific genomic modifications, is overwhelmingly finding use in academic laboratories. By contrast, Sangamo, which controls patents around ZFNs, is in Phase II with SB-728, a ZFN-based approach to modifying the gene encoding CCR5, the major co-receptor used by HIV to infect cells of the immune system. Moreover, Sangamo has entered into collaborative partnerships with Shire International and Biogen Idec, for human therapeutics; and it has licensed its technology to Dow AgroSciences and Sigma-Aldrich for agricultural and research applications.

    Editas and the other product-focused start-ups are still years, if not decades, from bringing a product to market. It is also still not clear that CRISPR technology will prove suitable for human therapeutics. Fundamental challenges yet to be worked out include its degree of specificity and the potential of single-guide RNAs to cause off-target effects in the human genome.

    However, while human therapeutic applications of gene editing steal the limelight, there are other sectors, including agriculture and specialty chemicals, in which the technology has advanced beyond the laboratory into product development and even onto the market.

  • Gene Editing Poised to Transform Agriculture

    In fact, gene editing is closer to transforming agricultural markets than human medical markets. To understand what is driving its application in agriculture, a few statistics are in order. The world’s population is set to grow from nearly 7 billion today to over 9 billion by 2050. The problem of overpopulation will be exacerbated by rising world food prices, by famines caused by both natural and political forces, by the overdevelopment of arable land, and by changing climate patterns. The Food and Agriculture Organization estimates the need for a 70% increase in crop production to simply maintain nutrition at today's levels.

    Gene editing offers the ability to modify critical traits in crops and animals: boosting food crop yields and nutrient quotients and making crops able to withstand blights, pests, or climatic extremes; and breeding hardier, disease-resistant farm animals with improved nutritional profiles. Moreover, food staples such as bananas, cassava, plantain, or potatoes, which are currently impervious or for which conventional breeding techniques are glacially slow, stand to benefit from gene editing.

    Other factors favoring the early adoption of gene editing in agriculture include the regulatory standards governing it. Gene editing has the potential of enabling a faster, less costly path to market. In the U.S., the U.S. Department of Agriculture (USDA) has recently ruled that some mutations made by MEGAs, ZFNs (e.g., Dow AgroSciences’ ZFN-derived maize lines) and TALEN (Cellectis plant sciences uses TALEN to improve potatoes, soybean, and other agricultural commodities) do not come under their regulatory authority. Therefore the preparation of a costly and time-consuming data package is not required. USDA expects to announce its position on the use of CRISPR/Cas9 to create new plant traits in the near future.

    Cibus, a San Diego-based agbio firm with a proprietary gene-editing platform, had its sulfonylurea herbicide tolerant canola approved first in the U.S. and more recently in Canada, making it the only example of a company founded on genomic editing to have reached market. Regulatory bodies in the U.S. and Europe consider its technology, Rapid Trait Development System (RTDS™), to be a natural form of targeted mutagenesis, and as such, excluded from an onerous and costly approval process. Cibus, which claims its RTDS platform is proven and reproducible, has other products in its pipeline.

    That distinction between the older, transgenic forms of breeding, in which foreign genetic material is introduced into the plant or animal, and on the other hand gene editing in which the native gene is modified in situ, involves more than just regulatory red tape. The older forms of transgenic genetic modification carry the status of genetically modified organism, or GMO, a politically controversial label that has hobbled the commercial development of agbio markets and, along with costly regulatory requirements, actually added to the cost of transgenic crop production. Although global transgenic crop acreage has seen 131% CAGR from 1996 to 2012 according to the International Service for the Acquisition of Agri-Biotech Applications (ISAAA), as of 2012 meaningful penetration into Europe, China, and other regions remains elusive because of GMO issues.

    Transgenic techniques have other drawbacks: the trait that is conferred might not be stable, are randomly inserted and thus may unintentionally disrupt native genes or may have linkage drag or reduced recombination rates near the inserted transgene which might take years of plant breeding to fix.

    By contrast, gene editing enables stable and heritable genomic changes quickly and easily without introducing foreign DNA. And although the patent situation particularly for CRISPR/CAS9 is still in the first inning and will likely take years to sort out.  Private companies like Cibus with proprietary technology have been able to build a patent estate permitting it to press ahead with product development. Unlike transgenesis, gene editing will enable researchers to modify genetic information in a natural way to bring out of the existing genome entirely new traits. And best of all, regulators have given it the green light to position its products as the non-GMO alternative.

  • An Agricultural Ecosystem Emerges

    Companies competing in the agricultural gene -editing space include firms providing tools and services, and those focused on product development and commercialization. The former group is composed of companies like Transposagen Biopharmaceuticals that serve both medical and agricultural markets with a broad variety of molecular biology products and services including gene editing. Examples of the latter group include Cibus, Precision Biosciences, Caribou Biosciences, Nova Synthetix, Cellectis, and Recombinetics. Only St. Paul, MN-based Recombinetics, which applies TALENs to the improvement of livestock, is a pure play agbio company. The others focus their gene-editing technology on various combinations of human therapeutics, agriculture, research use, and industrial products. Cibus, for instance, while primarily invested in agricultural gene editing, also applies its RTDS platform to the production of squalane.

    In addition, large, multinational chemical and life science companies have agricultural divisions that employ gene-editing technology acquired mostly through licensing arrangements with small specialist companies. Examples include Dow AgroSciences, DuPont Pioneer, Bayer CropSciences, and BASF Plant Sciences. Indeed, these global companies play a similar role to big pharma by providing funding, expertise, and geographic reach to small, innovative firms. 

    Not far behind agricultural applications for gene editing are the industrial applications. Companies like Nucelis, Sigma Aldrich, and Precision Biosciences are working on high-performance oils for use in cosmetics and lubricants, biofuels, flavorings, and other high-margin specialty chemicals. In June 2013, Cellectis reported that its scientists, using MEGAs and TALENs, successfully engineered the genome of single-celled photosynthetic algae called diatoms for the purpose of producing biofuel. Nucelis is close to market with its squalane oil, a fully hydrogenated form of squalene, the natural compound, which it can scale to commercial quantities using a microbial production platform.

    Gene editing has surely arrived. Despite the majority of media attention and investment dollars going to applications in human therapeutics, which no doubt promise the greatest return, the first commercial products will be agricultural and industrial. That’s where scientists and entrepreneurs are pioneering the production, the regulatory science, and the commercialization of products derived from gene editing.

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