Advances in Gene Editing Technologies

CRISPR technology is frequently on Frost & Sullivan’s radar as an important biotechnology tool, with applications as far-reaching as agriculture, oncology therapy, animal husbandry, basic research, and drug development. Read about the latest advancements.

Genetic engineering has fueled the imagination of writers and served as fodder for science fiction for decades. The 1990 novel (and 1993 movie) Jurassic Park, the embodiment of the possibilities of genetic engineering, actually far predated the technological advances that were required to make it possible. The watershed moment in the history of life science, and its implications for healthcare, happened in April 2003 when the Human Genome Project was officially declared complete, with the publishing of the entire human genome with a reported accuracy of 99.99%. This incredible scientific breakthrough, over a decade in the making, engaged the international research community and laid open the secrets that had been locked inside of us. The next logical step is the manipulation of this unlocked genomic information: the birth of genetic engineering.

Genome editing refers to the process of inserting, deleting or replacing a fragment of DNA with the aim of repairing a damaged genomic sequence. The tools that are used to effect genome editing are referred to as “molecular scissors”—enzymes that can cause site-specific cleavages so that the target gene sequences can be inserted. A few classes of nucleases or enzymes can cleave nucleotide sequences into smaller strands that are used to edit genomes: 

  • Zinc finger nucleases (ZFNs): These are artificial enzymes that are created to target specific sequences on a DNA strand, known as zinc DNA binding domains, found in eukaryotes. ZFNs can identify a specific sequence of DNA in the genome. 
  • Clustered regularly interspaced short palindromic repeats (CRISPRs): Bacteria have DNA sequences known as CRISPRs and proteins associated with CRISPRs (Cas). The CRISPR-Cas systems use DNA sequences derived from plasmids and phages to activate Cas endonucleases to neutralize the plasmids and phages through the RNA-guided, sequence-specific DNA cleavage, thus blocking their transmission and creating a simple acquired immunity. Due to its high flexibility and specificity, CRISPR technology is used for genome editing in different cell types and organisms. 
  • TALENs: Transcription activator-like effectors (TALEs) are proteins that are naturally found in plant bacterial genus Xanthomonas, and are used for single base recognition. Engineered TALEs are typically fused with a Fok 1 nuclease to form TALENs, which improve the specificity of cleavage. TALENs have been increasingly used in the agricultural industry to genetically engineer photosynthetic algae for the purposes of biofuel production, and to improve livestock by genetic editing to produce hornless cattle and disease-resistant pigs, for example.

CRISPR technology is frequently on Frost & Sullivan’s radar as an important biotechnology tool, with applications as far-reaching as agriculture, oncology therapy, animal husbandry, basic research, and drug development. Some of the key application areas are discussed here.

Agriculture: Genetically Modified Crops

Gene editing is used to increase crop production to meet the demands of the rising global population and combat uncertainties associated with climate change. The Food and Agriculture Organization of the United Nations (FAO) estimates that by 2050, food production will have to increase by more than 70% of the current global levels. Dow AgroSciences LLC (Indianapolis, Ind.) and Calyxt, Inc. (New Brighton, Minn.) have used ZFN and TALEN tools to create modified corn, potato and soybean lines. Calyxt’s portfolio of genome-edited agricultural products include high oleic soybeans (commercialized), cold storable potatoes that passed their first field trials two years ago, mildew-resistant wheat (undergoing pilot testing), high-fiber wheat, reduced-gluten wheat, and herbicide-tolerant soybeans and alfalfa (all currently under early-stage testing).  Calyxt, through its parent company, France-based Cellectis, has patented the rights to engineering plant genomes using CRISPR/Cas9 systems, and has developed solutions to yield better crop production. 

Cibus US LLC (San Diego, Calif.) is an agri-biotechnology company that has used its proprietary gene editing technique called Rapid Trait Development System (RTDS) to create sulfonylurea herbicide-tolerant canola oil. Cibus’ new product, SU Canola, has received regulatory clearance in the United States and Canada.

Industrial Applications

Gene editing is being used in the development of industrial commodities such as biofuel, high- performance oils, cosmetics products, flavoring, and specialty chemicals. Cibus’ sister company, Nucelis, uses the RTDS technology platform to develop squalane, an important ingredient for cosmetic products. The company also applies the RTDS technology to modify yeast, bacteria, plants and algae for the production of nutritional products, such as vitamin D2, ergosterol and yeast-based flour. 

Farm Applications: Increasing Food Yield

Gene editing has been used in the development of livestock for food production (meat, milk and eggs). Conventional animal rearing approaches, such as selective mating, have proven to be imprecise, unreliable and time-consuming, and often result in weak offspring. 

Recombinetics (St. Paul, Minn.), an agri-biotech start-up, has used gene editing techniques to modify specific phenotypic traits that are present in cattle, such as eliminating horns. Cattle are often subjected to a painful de-horning process; the elimination of horns altogether is expected to make the use of dairy cattle more humane. Similar genetic modification experiments are being conducted on salmon to make them more immune to disease. 

Clinical Applications: The Final Frontier

Gene editing is utilized in the development of novel drugs (gene therapies) to treat cancer and rare disorders. With an increase in genetic information, a whole gene therapy industry has capitalized on the potential in this space. For infectious diseases, with gene editing a whole range of programmable nucleases for antivirals can be created. The area that has received most attention for antiviral-based products is HIV. A range of breakthroughs have been made in genetically modifying long terminal repeats, or LTRs, with Cas9 to reduce the expression of HIV genes.  

In September 2017, Paris-based Eligo Biosciences received $20 million in Series A funding from a clutch of private investors to help the company in its efforts to develop a CRISPR-enabled drug candidate that would lead the fight against infectious diseases. Proof-of-concept studies indicate that the drug candidate has been successful in selectively killing bacteria—“sniper shots,” as the company refers to them—in the gut. However, the company feels that the technology is scalable, and that the true potential lies in using the platform to kill antibiotic- resistant bacteria.

Naturally, given the regulatory hurdles involved in bringing these technologies to market— not to mention the ethical concerns and technological difficulties in creating them in the first place—a number of companies have a lengthy pipeline of products, even if they don’t have any on the market yet. CRISPR Therapeutics (Cambridge, Mass.) has a number of projects underway studying the efficacy of using the CRISPR platform in diseases such as sickle cell anemia, muscular dystrophy, hemophilia and cystic fibrosis. 

The Road Ahead

The lowest-hanging fruit for gene editing technologies for therapeutic use is in research and development of drugs. Genetic engineering can help create research models that can then be used to test the validity and efficacy of drugs, greatly accelerating product development and minimizing costs involved in clinical research. 

While ethical concerns and social norms would limit outlandish applications of gene editing (we have to resign ourselves to watching inferior Jurassic Park sequels), there could be interesting and globally useful applications of gene editing. Mosquitoes that do not spread malaria and dengue, for instance, would make the lives of millions infinitely better. That could happen in our lifetime. 

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