Protein engineering

The key for Cellectis is to engineer Meganucleases that are specific to the targeted site, so as to create “tailor-made” meganucleases for each gene of interest. This ability to produce a wide range of molecules specific to the genes targeted is the technological gamble which led to the creation of Cellectis. The gamble paid off in 2004, when the company’s researchers achieved the industrial-scale modification of the recognition site of an existing meganuclease, without the resulting new molecule losing its ability to break the DNA and stimulate recombination.

Within the structures of the known meganucleases, the researchers identified the areas responsible for the “DNA scissors” function and the areas that correspond to the recognition of specific DNA sites. Cellectis then modified this latter part so as to generate variants that retain their cutting activity but bind to a different region of the genome. Cellectis currently has a large bank of proteins with over 20,000 motifs that can be combined to obtain chimeric proteins capable of binding to various regions of the DNA molecule.

When a new project requires a new meganuclease so that a different site in the Genome can be manipulated, Cellectis’ teams create a meganuclease from this Protein bank. In the same way as a child’s building blocks, a red brick and a yellow brick together create a new construction. The bricks are the parts of the Genome that code for the various target areas. Scientists identify the molecules whose targets are close to the target aimed for. They then take the corresponding areas on the Genome and combine them to create a new molecule with the specific recognition site required. The activity of each newly created meganuclease is tested in a series of functional trials developed by Cellectis.

All this creative and analytical work is carried out by the Cellectis Platform. This is where all the enzymes used and sold by Cellectis are made, from A to Z. The Platform team creates quality meganucleases, while complying with a precise set of specifications for each Cellectis partner. Thanks to its many robots, the Platform is able to measure the activity of a high number of enzymes. Indeed, it is able to run up to one million of tests a week. The data is then treated, analyzed and used to design molecules suiting each project. The Platform enables Cellectis to validate and execute its orders, finding a maximum of solutions for a maximum of clients. Moreover, by carrying out its research work, the Platform is able to expand the database, enhancing Cellectis’ knowledge and scientific expertise.