Start-up Profiles

Published online: 25 July 2005, doi:10.1038/bioent870

Commercializing synthetic biology

*Ken Howard Wilan is a contributing writer for Nature Biotechnology based in Westborough, Massachusetts, USA. kenhoward@mindspring.com

Amyris Biotechnologies and Codon Devices offer entrepreneurs and investors a hint of the commercial strategies to come in synthetic biology commercialization.

University of California, Berkeley's Jay Keasling has become a common denominator in the synthetic biology field. His quest: bridge the considerable gap between science and product development. Peg Skorpinski

What does the antimalarial drug artemisinin, extracted from the wormwood plant, have in common with multiplex gene synthesis? The answer is two companies cofounded by University of California, Berkeley's Jay Keasling. Together, these two companies represent in many ways the commercial hopes of the emerging field of synthetic biology.

Amyris Biotechnologies of Emeryville, California, and Codon Devices in Cambridge, Massachusetts, both founded in 2004, represent a convergence of technologies that could allow the large-scale, relatively inexpensive and fast creation of engineered genetic pathways as a tool for R&D as well as a method for producing drugs. Under the rather broad moniker of synthetic biology, these companies are attempting to optimize gene function and introduce new regulatory features into metabolic pathways.

"We're at the right place and right time" to commercialize synthetic biology, says Keasling, professor of chemical engineering and bioengineering at Berkeley and director of the newly formed Berkeley Center for Synthetic Biology, run jointly by Lawrence Berkeley National Laboratory and the California Institute for Quantitative Biomedical Research. "There's a lot of DNA sequences out there, computational power, advanced molecular biology and databases of metabolic pathways. It's the right time for everything to be coalescing."

Hoping for proof of concept

Amyris Biotechnologies (see Box 1) is harnessing that power to train Escherichia coli, via molecular biology, to make artemisinin, a very effective antimalarial agent but one that is expensive on an industrial scale to harvest, extract and purify from its wormwood plant source.

The company is built on technology from Keasling's lab to genetically modify microbes to produce a class of compounds known as terpenoids¹, a starting point for a number of possible therapeutics and industrial chemicals (Figure 1), says Amyris president Kinkead Reiling. Synthetically producing artemisinin by genetic engineering and fermentation and scaling up the production to a commercial level will be the company's starting point to expand into synthesis of other compounds, he says.

Fig. 1

		Tweaking pathways Amyris Biotechnologies of Emeryville, California aims to tweak various metabolic pathways and introduce them into microbes to create microbial chemical factories to produce products for the healthcare, chemical and energy industries.		Image Amyris Biotechnologies, Emeryville, California

The company's approach was promising enough to interest the Seattle, Washington-based Bill & Melinda Gates Foundation. The foundation sees the method as a way to get more artemisinin, in short supply, to people primarily in Africa and Asia, where each year between 300 and 500 million people are infected with malaria and 1.5 million die. The Institute for OneWorld Health, a nonprofit pharmaceutical company based in San Francisco, received a grant of $42.6 million over five years, of which $12.5 million will go to Amyris.

Although the company will not make a profit from any sale of artemisinin, the project will go a long way toward validating synthetic biology as a drug development platform. For Amyris, the money allows the company to scale the production towards commercial levels while building its core technology, says Reiling. He says they are slated to finish their part of the process at the end of 2007 when OneWorld Health begins commercial development of the medicine based on Amyris' work.

In the meantime, the company will seek out other potential partners, possibly including pharmaceutical companies as well as industrial and nutraceutical companies that might be interested in their technology platform, says Reiling. They are also considering seeking venture capital. Although the company must now prove that their microbes can be turned into factories producing commercial quantities of product, they have already shown their technology can coax chemicals from microbes and have thus taken a critical step beyond potential competitors.

Made-to-order genes

Keasling's other venture into commercializing synthetic biology is Codon Devices (see Box 2). In addition to Keasling, Codon's scientific advisors include other synthetic biology pioneers like George Church from Harvard University and Drew Endy and Joseph Jacobson of MIT.

It was Codon's technology, much of which is based on work by Church and colleagues², and its high-wattage advisors and founders that enticed blue-chip venture capitalists Kleiner Perkins Caufield & Byers of Menlo Park, California, and Flagship Ventures in Cambridge, Massachusetts, to join as founders and, with Alloy Ventures of Palo Alto, California, invest $13 million. Not bad for a startup in an emerging field.

Codon is making a play not just to offer oligo design and assemblage faster than currently available, but to do so with a speed and cost savings that will transform the way science is done. If the technology pans out, say industry observers, it will offer partners and both academic and industry customers the ability to quickly and cheaply make sequences and genes from scratch.

In this way the company could emulate the model of Foster City, California-based Applied Biosystems, which by introducing commercial high-throughput sequence machines, as well as the reagents and methods to use them, not only changed research methods but also made itself a lot of money. It says a bit about Codon that former Applied Biosystems president Michael Hunkapiller, now with Alloy Ventures, sits on Codon's board of directors as well as its scientific advisory board.

Follow the IP

Codon's future rests largely on its collection of its own or licensed intellectual property (IP) for its platform to design, construct and assemble large strings of oligonucleotides. The technology will be used to design and engineer proteins, vaccines and drugs for human therapy and possibly for bioprocesses and the energy industry, says Codon CEO Samir Kaul, a cofounder from Flagship Ventures. He says the company will begin generating revenue by the end of 2005, though he declined to reveal potential partners or customers or the source of specific IP for the company, saying the company is still in "stealth" mode. These are big promises for a startup.

There are, after all, already gene synthesis companies like Bothell, Washington-based Blue Heron Biotechnology, GeneArt in Regensburg, Germany, and Menlo Park, California-based DNA 2.0, with a head start in the field. Also, J. Craig Venter recently launched his own company, Synthetic Genomics based in Rockville, Maryland, that aims to use synthetic biology as a platform for developing products that may address many of the same markets.

What does Codon have that these other firms do not? With the company in stealth mode, it's impossible to know, exactly. But, there are those who are familiar with the company—and do not have a commercial stake in Codon—who like this company's chances.

"Codon Devices is developing the next generation of tools and approaches," says Karl Handelsman, a general partner with CMEA Ventures in San Francisco. "All the other companies have customers today and are spending most of their effort meeting customers at hand. Codon is trying to leap frog that using parallel synthesis of oligos on substrates."

Parallel synthesis promises to lower overall costs compared to standard oligo synthesis by using small amounts of oligos more cheaply, says Handelsman. In this way, Codon has the opportunity to jump into the market with the promise of technology that offers faster and more varied gene engineering without the issue of overhauling or scrapping legacy systems, he says.

Succeeding as a business, however, may hinge on how much patent protection Codon has around its technologies as well as what IP for other methods are held by other parties, says Paul Pospisil, a partner in Atlas Ventures in Waltham, Massachusetts. With Codon holding its IP close to its vest, observers outside the company will have to wait to see how it unfolds.

References

1. Martin, V.J.J. et al. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotechol. 21, 796–802 (2003).

2. Tian, J. et al. Accurate multiplex gene synthesis from programmable DNA microchips. Nature 432, 1050–1054 (2004).