Synthego’s CEO and co-founder Paul Dabrowski
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.

“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 increasingly 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,” Dabrowski 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 engage in gene editing.

After launching CRISPRevolution synthetic guide RNA kits to simplify CRISPR gene editing in the lab, Synthego recently unveiled its Engineered Cell product portfolio. “Our engineered cells are a unique offering,” Dabrowski says. After launching its CRISPR kits, Synthego built on top of that “full stack” genome engineering infrastructure 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 interest in larger business partnerships,” and the company is growing rapidly, going from 50 to 130 employees in about 18 months to support 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 become comfortable with the editing process.”

“We’ve been working to create informatics 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 online tool is still committed to knockouts,” but he hints that focus will be expanding.

A lot of work is going into developing increasingly efficient algorithms. They are used internally to improve cell engineering workflow 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 uses proprietary synthesis technology
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 algorithms are the backbone that lets the company offer a money-back guarantee of high editing efficiency—typically defined as the percentage of cells modified in any way by CRISPR. Dabrowski says that, for Synthego, this means that 50% of the cells in a cell pool will reflect the intended 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 successfully edited, including many that other researchers found difficult or even unsuitable for CRISPR modifications. If Synthego’s engineers can’t successfully engineer a cell line, it doesn’t appear in the list, he stresses.

Using Synthego’s engineered cell lines, researchers can test the regulatory pathway or create a disease model for specific genetic variants. 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 engineering. It’s a common term in the software world, where Synthego co-founders Paul and Michael Dabrowski got their start as engineers 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 modeling to determine the most effective gRNAs, creating extremely high-quality gRNA and then performing sophisticated edits. “All these things fit together,” Dabrowski declares. Our philosophy is to make full-stack genome engineering solutions very accessible to scientists.” Consequently, he expects researchers to make high-quality genome edits quickly and effectively, saving significant time (possibly several weeks) on each editing project.

Advancing Genetic Medicine to the Clinic

Dabrowski’s overarching goal is to create an ecosystem in which gene editing becomes a clinical tool to actually cure genetic disorders. “The first gene and cell therapies are coming on the market now. Most are priced between $800,000 and $1.5 million,” he says. Neither patients nor payers can afford them. “We think that if a few areas of the R&D and commercialization process can be changed, a new area of medicine with cures that have costs of $10,000 per patient can be created.” By advancing a full-stack genome engineering mindset, he says, results will be more predictable, easier to generate, and will incur fewer delays. In that way, clinical gene and cell therapies will become practical for researchers to develop.

There are two steps at which Synthego can help the industry achieve that goal. “The first is R&D, using engineered cells and bioinformatics to choose the correct targets. We have those products,” he says.

“The second is manufacturing the therapy,” he continues. That requires cGMP-grade materials. “We’re ramping up the ability to create cGMP gRNAs for customers who are looking to go into the clinic.”

That’s especially exciting, he explains, because it suggests the industry surrounding CRISPR is mature enough to branch out from pure research and begin entering the therapeutic space. That in turn moves gene and cell therapies closer to mainstream use. It doesn’t hurt that industry successes also increase Synthego’s potential customer base.

Synthego 2024

Dabrowski equates gene editing to a typewriter today. Within five years he wants it to be a word processor, with all the inherent improvements in ease of use and efficiency. In 2024, “it would be wonderful to be able to perform any type of genetic manipulation for our customers, perturbing 10 to 20 genes effectively and showing that the cell lines work.”

On the therapeutic side, Dabrowski wants Synthego to participate in multiple clinical trials to help advance gene- and cell-based therapies. Forming partnerships is part of the plan, but that, he says, is too early to discuss.

“A lot of technical progress needs to be made to continue improving the field,” he says. At Synthego, that means more hiring. Its staff has grown roughly 250% in the past 18 months, and that doesn’t appear to be slowing. The company is hiring in all departments. “We’re looking for qualified, motivated individuals who are in the right place at the right time and are interested in joining a mission-driven company,” he says. He’s looking across the board at IT specialists, biologists, chemists, and others, with the expectation of continuing a similar rate of growth.

Supporting such rapid growth risks diverting attention from the science to the business systems and processes that may be sidestepped when organizations are small, but that are vital to the smooth operations of larger companies. If Dabrowski is concerned about growth pains, he’s keeping it to himself.

Synthego

Location: 3696-A Haven Avenue, Redwood City, CA 94063

Phone: (650) 206-4011

Website: www.synthego.com

Principal: Paul Dabrowski, CEO

Number of Employees: 130

Focus: Synthego is a genome engineering company based on CRISPR technology. It performs editing in-house and also develops tools and cell lines to help researchers make gene and cell modifications themselves.

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