Next-Gen Gene Synthesis Will Accelerate Biopharmaceutical Design and Development

As the biopharmaceutical revolution has taken off, pharmaceutical and biotechnology companies are finding novel ways to design and develop these protein- or nucleic acid-based drugs. One of the most promising techniques involves synthetic biology. This pivotal tool in biological engineering allows drug developers to zoom in to the DNA level, recode the bases for a specific purpose and test the resulting DNA sequence for optimal efficacy as a possible biotherapeutic agent.

The pharmaceutical community has already seen tremendous success with this approach. Biopharmaceuticals produced in this manner include hormones, growth factors and cytokines such as interferons and interleukins. Much of this work has been accomplished using recombinant DNA technology, an approach that typically relies on a host organism to replicate and produce the desired DNA fragments.

Synthetic biology currently suffers the limitations of being a low-throughput, high-error technique. This serves as a major rate-limiting step in designing new biopharmaceuticals. However, the advent of a new gene synthesis technology promises to streamline the use of synthetic biology and enable scientists to dramatically increase the number of biopharmaceuticals they can design, test and redesign in a short period of time.

A number of recent advances show the utility of synthetic biology in biopharmaceutical development. One particularly well-known project comes from Amyris, a synthetic biology company that designed yeast strains to produce artemisinic acid, which can be used to create the antimalarial therapeutic artemisinin. While proof of principle was reported some time ago, just this year Sanofi has begun using this approach to produce artemisinin at industrial scale; by next year, the company anticipates producing as many as 150 million treatments in this therapeutic form. This replaces the standard but expensive and time-intensive process of extracting artemisinin from a plant. Indeed, increased access to life-saving drugs is a real benefit of manufacturing compounds like this one at industrial scale through microbes.

In addition to engineering the drug itself, a great deal of work has gone into improving the host organism as well. While much of the industry relies on the yeast Saccharomyces cerevisiae for expressing biopharmaceuticals, recent activity has demonstrated the merits of using the methylotrophic yeast Pichia pastoris instead. Scientists created custom glycosyltransferases and glycosidases for the organism, which served as just one part of the process used to achieve humanized glycosylation in Pichia. Other steps included removing the relevant native genes and introducing pathways and other elements not normally found in the organism. This work has already begun to pay off as the U.S. Food and Drug Administration recently approved Dyax’s Kalbitor, the first biopharmaceutical produced from Pichia.

Although synthetic biology has seen rapid uptake in the past decade, an underlying technique that facilitates the use of synthetic biology remains limited by the artisanal nature of its production. The standard methods for gene synthesis—or producing the DNA needed in synthetic biology work—are tedious, manual, and prone to error. They are not exponentially scalable, so expanded use of synthetic biology does not translate to lower costs or higher throughput.

But next-generation gene synthesis promises to alleviate these problems. Developed by academic scientists, this method improves the quality, accuracy and length of constructed DNA. Based on advances from George Church from Harvard University, Drew Endy from Stanford University and Joseph Jacobson from the Massachusetts Institute of Technology, next-gen gene synthesis relies on recent innovations in synthetic biology to build better DNA. The technology and process around it have been commercialized by Gen9, a company based in Cambridge, Mass.

Gen9 has built its silicon chip-based BioFab platform using massively parallel gene synthesis and a novel error-correction pipeline. Today, the company offers lower-cost, longer, more accurate DNA constructs. Because this method can scale at an exponential level, capacity can be added quickly and at low cost. The platform can currently generate tens of thousands of DNA constructs per year; by 2014, Gen9 expects to dramatically expand the world’s capacity for gene synthesis.

That achievement will have real benefit to scientists in pharma and biotech. With reliable access to longer, higher-accuracy, lower-cost gene constructs, scientists can not only test far more drug and organism designs than ever, but they can also alter longer stretches of DNA—engineering at the gene or pathway scale instead of short DNA fragments.

Next-generation gene synthesis stands to transform the biopharmaceutical design and development pipeline by providing, for the first time, ready access to long, reliable DNA constructs that facilitate massively parallel screening and tuning of potential drugs and host organisms. With this improvement, synthetic biology can become an important workhorse in the pharmaceutical and biotechnology research & development realm.

Kevin Munnelly is the CEO of Cambridge-Mass.-based Gen9.