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Sep 1, 2014 (Vol. 34, No. 15)

Accelerating Gene Synthesis

Gen9 Automates DNA Construct Production via the Use of Next-Generation Techniques

  • Low-cost, high-quality synthetic DNA will unlock the potential of the biopharmaceutical, industrial biotech, and chemical industries, helping them capitalize on the advances of the genomic revolution to develop innovative products faster than ever and much less expensively.

    Gen9 believes it has found its niche in the synthetic nucleotide market by focusing on the automated production of DNA constructs.

    “We’re democratizing synthetic biology, making it more accessible,” says Kevin Munnelly, president and CEO. “Our scalable technology allows us to make genes, pathways, and genomes at a much larger scale.”

    Throughout academia and even industry, most synthetic genes are made by Ph.D.-level scientists, one at a time, in a time-consuming serial process, according to Munnelly. Gen9 maintains that its approach streamlines the process. “By combining liquid handling and microfluidics, we can build tens of thousands of genes at a time in a highly parallel process,” says Munnelly. The methodology is based upon a scalable, chip-based starting material, followed by enzymatic error correction and in vitro cloning.

    Traditionally, small DNA fragments are more than 99% accurate, but they still have some margin of error. As the fragments become larger, the errors become more prevalent and problematic.

    “Enzymatic error correction helps identify errors when making the oligos and either filters them or enables other enzymes to correct them. The enzyme itself allows this,” Munnelly points out. “It looks at the sequences and identifies when the bases don’t match perfectly.”

  • Benefits

    Historically, the cost of developing synthetic DNA has been exorbitantly expensive—running to tens of millions of dollars to build a small genome. “We can do that for a fraction of the cost,” claims Munnelly.

    As the price comes down, the number of things that can be accomplished multiplies and leads to more and better products. For example, “The ability to access large quantities of high-quality synthetic DNA inexpensively lets researchers create and test many versions of genes or pathways,” continues Munnelly. “This lets scientists make improved drugs faster and identify better binding events or properties. It will enable the creation of whole new application areas.”

    Gen9 further encourages the use of synthetic DNA through an annual competition with a prize of one million bases. Principal investigator Tanja Kortemme, Ph.D., at the University of California–San Francisco won last spring with a metabolic engineering project focused around cell signaling. Her goal is to design proteins that either interrupt or take advantage of signaling pathways.

    Other researchers throughout the country are investigating new ways to conduct drug discovery by investigating protein-to-protein applications in vivo and to carry out projects in regenerative medicine and biosensors.

    Gen9’s newest product, GeneByte Plus DNA constructs, was commercialized in July. The product is the newest in the Gen9 product portfolio, with lengths from 3,000 to 10,000 double-stranded base pairs. It is designed for metabolic pathway engineering.

    The GeneByte™ DNA constructs, already out, come in lengths between 1,000 and 3,000 base pairs, while the GeneBit™ DNA constructs are synthesized in lengths between 500 and 1,000 base pairs.

    Gen9 also recently launched a variant library for peptide and antibody engineering. As Munnelly points out, “Most variant libraries on the market today are made by mutagenesis. Gen9’s is the first rationally designed library. And, because we’re making so many oligos that make so many genes, we can make many variations in small parts of the genes and put them together combinatorially, with up to 1010 variations in one reaction.”

    Munnelly says he plans to launch other variant libraries throughout the year. Next will be a metabolic pathway library that enables gene shuffling and, therefore, the ability to optimize constructs by changing promoters. Gen9 also is developing “scanning libraries that mutate genes systematically at every base all the way across the gene,” he adds. Initial applications are for protein, antibody, and enzyme engineering for pharmaceutical and industrial uses.

  • A Gene in Every Home

    Click Image To Enlarge +
    Gene synthesis historically has been expensive and time consuming. As new technologies continue to lower the price, scientists will be able to undertake an increasing number of genetic pathway projects that will serve to accelerate the progress of their research. [Wichy/shutterstock.com]

    Moving forward, notes Munnelly, Gen9’s focus is to improve the customer experience. “We’re developing infrastructure to capture market share,” he explains. Specifically, Gen9 is deploying gene pathway design software and a new customer portal to simplify the use of the Gen9 BioFab® process for in silico design and fabrication. “We’re also incorporating more public repositories so customers have more predesigned parts from which to select.”

    This is all designed to help the industry move toward genome engineering—developing de novo scaffolds as better hosts, for example.

    Gen9 also is an active member of the International Gene Synthesis Consortium (IGSC), which coordinates best practice development to enhance biosecurity while advancing the applications of synthetic DNA. It expects to become one of the IGSC’s largest developers.

    “Eventually, we want a Gen9 gene in every home,” he says, explaining that synthetic DNA will be integral in developing better biotherapeutics as well as fuels, food products, plastics, detergents, and fragrances. “Synthetic DNA can revolutionize how these targets are developed and produced.”

    Since beginning operations in 2010, Gen9 has layered an entrepreneurial management approach atop its scientific expertise. This has brought a certain business savvy to Gen9 that many young companies lack, maintains Munnelly, who adds that Gen9 has advanced products from early-stage development to commercialization while attracting the right financing at the right time.

    “We have a variety of types of investors,” Munnelly says, including super angels and partners. Agilent, for example, is both a strategic supplier and an investor.

  • Gen 9

    Location: 840 Memorial Drive, Fifth Floor, Cambridge, MA 02139

    Phone: 617-250-8433

    Website: www.gen9bio.com

    Principal: Kevin Munnelly, President and CEO

    Number of Employees: 40

    Focus: Gen9 provides DNA constructs using next-generation DNA synthesis.

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