Genetic Engineering & Biotechnology News

DEC 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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6 | DECEMBER 2018 | Genetic Engineering & Biotechnology News | GENengnews.com Gail Dutton "People are transitioning from wanting to learn about CRISPR to wanting to use it," says Paul Dabrowski, CEO of Synthego. A year and a half ago, when the company was first profiled in GEN, he estimated that no more than 33% of those who could use CRISPR were using it. "Now that's closer to 40%. There's been a shift in mindset," he notes, that's moving usage from the early adopter phase to an early majority. CRISPR is becoming a mainstream tool for an in- creasingly broad user base, and is beginning to be used for therapeutic development. "It's attracting researchers in new industries and fields who wouldn't use older generation [gene editing] tools like zinc fingers," he adds. That's good news for Synthego, whose tools are helping to drive that shift. Overall, "the editing tools are better today," Dab- rowski says, but specialized knowledge is still needed for advanced editing. Synthego is working to flatten that learning curve to make it practical for more researchers to en- gage in gene editing. After launching CRISPRevolution syn- thetic guide RNA kits to simplify CRISPR gene editing in the lab, Synthego recently unveiled its Engineered Cell product portfo- lio. "Our engineered cells are a unique of- fering," Dabrowski says. After launching its CRISPR kits, Synthego built on top of that "full stack" genome engineering infrastruc- ture to provide in-house gene editing for customers. Synthego also provides analysis and design of gene edits, powered by its bioinformatics engine, to select guide RNA (gRNA) and to better predict the outcomes of any perturbations. In terms of business, "there's a lot of inter- est in larger business partnerships," and the company is growing rapidly, going from 50 to 130 employees in about 18 months to sup- port customers in more than 40 countries. The State of Gene Editing "For complex modifications like tagging or knocking in a gene, there's still a lot that's unknown, both in the field and in relation to the tools," Dabrowski admits. "It takes a long time for scientists to get up to speed. Many scientists often spend six months in the lab to develop the specific knowledge they need for individual cell types and to be- come comfortable with the editing process." "We've been working to create informat- ics models to predict outcomes via a score, so users don't have to search to get a genetic edit to work," he says. Currently, "our on- line tool is still committed to knockouts," but he hints that focus will be expanding. A lot of work is going into developing in- creasingly efficient algorithms. They are used internally to improve cell engineering work- flow to let the company modify cells faster and with greater success. The other aspect of this work involving encoding algorithms to determine the best tools to use and ways to use them, and also to design those tools to be accessible even to researchers who aren't yet CRISPR experts. Synthego's algorithms are the backbone that lets the company offer a money-back guarantee of high editing efficiency—typi- cally defined as the percentage of cells modi- fied in any way by CRISPR. Dabrowski says that, for Synthego, this means that 50% of the cells in a cell pool will reflect the in- tended type of modification (for example, a single gene functionality knockout). "This is a more rigorous definition," he asserts, than that common in the industry. That guarantee comes with caveats. For example, it is limited to a list of certain cell lines. The list, however, contains several hundreds of cell lines that Synthego has suc- cessfully edited, including many that other researchers found difficult or even unsuitable for CRISPR modifications. If Synthego's en- gineers can't successfully engineer a cell line, it doesn't appear in the list, he stresses. Using Synthego's engineered cell lines, re- searchers can test the regulatory pathway or create a disease model for specific genetic vari- ants. For example, Dabrowski says, "We can engineer the variant into a wild-type cell line to demonstrate how a normal cell line changes its behavior in the presence of a disease state." The results Synthego is achieving are the result of a process known as full-stack engi- neering. It's a common term in the software world, where Synthego co-founders Paul and Michael Dabrowski got their start as en- gineers at SpaceX. In that industry, it means optimizing the firmware that controls the computers, the operating system (OS), and the applications that run on the OS. "You end up with a system that works very well," Dabrowski points out. In the case of genome editing, full-stack engineering means using predictive model- ing to determine the most effective gRNAs, creating extremely high-quality gRNA and Synthego's Software and RNA Kits Are Designed to Facilitate Scienti•c Discovery and Speed Therapeutic Development Full-Stack Genome Engineering Can Simplify CRISPR Workˆows On Your Radar Synthego's CRISPRevolution kits provide access to fully synthetic RNA for high-delity editing and increased precision in genome engineering. For example, the company provides a Synthetic sgRNA Kit, a Gene Knockout Kit, and a Synthetic cr:tracrRNA Kit. Synthego uses proprietary synthesis technology to chemically synthesize high-quality RNA oligonucleotides in either the single-guide RNA (sgRNA) or two-part cr:tracrRNA formats for S. pyogenes Cas9 CRISPR editing. Synthego's CEO and co-founder Paul Dabrowski used to be lead digital designer at SpaceX. Now that he's applying his engineering talents to intracellular space, he hopes to contribute to dramatic cost reductions in gene and cell therapies.

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