Constructing metabolic pathways -making the impossible possible: scaling from discovery to manufacturing with Conagen
Making the impossible possible: scaling from discovery to manufacturing with Conagen
April 9, 2019
This article is brought to you by Conagen Inc. Conagen is an ingredient innovation platform that uses modern synthetic biology tools for the biological production of high-value, plant-based and non-GMO ingredients for the food, nutrition, pharmaceutical and renewable materials industries. The company brings together the most advanced integration of scalable manufacturing with industry leading- and cutting-edge R&D capabilities. Conagen is truly differentiated within food ingredient-biotechnology industry. To learn more, visit conagen-inc.com
Entrepreneurs have great ideas. Synthetic biology companies create amazing products based on proven science. These things take a lot of work, of course, but even more is required to turn a great idea into a profit-turning product. The critical challenge all companies eventually face on their path to profit is scaling. And, like it or not, scaling is critical for securing investors, as many consider a company’s potential to scale a critical part of making funding decisions.
The ability to translate from discovery to manufacturing is a clear and significant strategic advantage for any company — yet the journey is often long and arduous, not to mention expensive. Add to that a complex regulatory and IP field. Altogether, this requires most companies to outsource multiple parts of the process to bring a product to market.
Full-scale, vertically integrated processes – in a lean package
But one company has perfected the process. Boston-based Conagen, Inc. is successfully helping clients to commercialize about 35 products through a unique “integrated manufacturing” process that rapidly brings products from design to industrial-scale fermentation — without outsourcing. Their expertise, together with their market knowledge and regulatory experience, uniquely positions Conagen as a full-spectrum service provider that can help companies navigate the scaling, regulatory, and market challenges to producing a revenue-generating product.
Critically, companies using Conagen’s services only need to outsource to one entity that utilizes full-scale, vertically integrated processes — drastically reducing time to market, and the pain involved with getting there.
So, how do they do it?
The secret: platforms, platforms, platforms
If you attended SynBioBeta 2018 in San Francisco last October, you may have already had a taste of Conagen’s processes — quite literally. At the conference, Conagen’s Manager of Scientific Operations, Matt Mattozzi, treated attendees to a taste of peach — not the fruit, but a small molecule (the naturally peach-flavored gamma-decalactone, to be precise) that went from bench-scale fermentation to commercial-scale production in roughly six months. This is especially impressive considering the challenges that had to be addressed in such a short time-frame: identifying the right organism for the job, getting the fermentation process to work at an industrial scale, and meeting regulatory requirements so that the product could even be served to consumers at the conference.
At the crux of it all, according to Conagen’s CEO Oliver Yu, is platforms. The lactone metabolic pathway platform used for producing the gamma-decalactone peach flavored molecule is just one of many developed by Conagen. The platforms, ranging from terpenoids and lipids to amino acids and phenolics — each with their own product-specific variations — all have one characteristic in common: the same platform used for producing a single small molecule such as gamma-decalactone is optimized for a number of different organisms. This is critical, not only because your organism of choice may not produce the desired amount of product at scale, but also for increasing speed to market, says Mattozzi.
Conagen’s platforms are focused on metabolic pathways because cloning genes is essentially not a limitation anymore, according to Mattozzi. What is challenging, he says, is figuring out whether there are any missing enzymes in your metabolic pathway — and figuring out how to construct your metabolic pathway.
“Often you’ll have some ideas, but you don’t know all of the genes that are responsible for all of the different pathways,” he says. “And when constructing a pathway, certain aspects like the number of genes and their orders can make a huge difference in the final outcome… and it can be very different at the laboratory versus production scales.”
All of these factors are critical when determining how to construct a metabolic pathway — and all of these factors are tackled with Conagen’s metabolic pathway platforms.
Gene discovery: if you want a swimming bird, start with a duck
The backbone piece that makes everything work is Conagen’s Gene Discovery Program — essentially a database of genes with known function. They collect information for their database through environmental samples, samples of their own products, or samples of natural product sourced from their suppliers — mining genes along the way. This is an especially useful approach because while there may be thousands of ways to get to your desired product, it’s a lot easier to optimize a reaction that already exists naturally and that can simply be built upon. As Yu likes to say, “if you’re trying to make a bird that swims, why start with a chicken?”
This is the process that Conagen used to optimize metabolic pathways to produce RebM — the molecule behind the next generation of stevia-based sweeteners. The major molecular component of stevia leaf is a rebaudioside called stevioside; however, trace amounts of other rebaudiosides are what give the extract its sweet flavor. The rebaudioside with the best flavor profile is RebM. By starting with the natural enzymatic pathway that converts stevioside to RebM, the Conagen team used their gene discovery process to identify and optimize several other pathways to RebM. The resulting commercial product, BESTEVIA® Reb M stevia leaf sweetener, can be found in multiple food products found in local grocery stores, including yogurt and carbonated beverages.
Navigating the regulatory space: a little know-how goes a long way
But in order for a product such as BESTEVIA® Reb M stevia leaf sweetener to reach shoppers at Whole Foods, developing a product and identifying a market are not enough. There are a slew of regulatory and IP measures that must be met before any product can reach consumers. When it comes to metabolic engineering like that facilitated by Conagen, everything from the order of the genes to the regulatory landscape of the final product is a critical part of the landscape — and is something that Conagen has been dealing with for a long time.
Any company producing molecules intended for human consumption also needs to meet several international regulatory standards, from the United States Food and Drug Administration to any local regulatory organizations required for international distribution. And, different microbial strains have different regulatory controls. With around 20 platform strains in their portfolio already, Conagen is accustomed to navigating the regulatory quagmire. In fact, it was because of their regulatory structure that the SynBioBeta peach taste test happened only six months after product conception by scientists — many of Conagen’s small molecules have regulatory approval long before they become ingredients in commercial products.
“There are a lot of things that I think a lot of people thinking about synthetic biology forget, and these are things that we’ve had to think about while getting our processes to market already,” says Mattozzi. “We definitely have the expertise in this. And we’ve been through this pain before.”
The process of scaling a product from concept to market is often long and arduous. Perhaps few enterprises understand this challenge. Conagen is well-equipped to help its clients to navigate the process. With their experience, platforms and speed they can help both enterprises and entrepreneurs do what they’re best at: taking great ideas, and introducing them to the world.
A trained microbiologist with over 7 years of experience in microbiome research, Dr. Embriette Hyde is passionate about bringing science to the public. She is currently working as Managing Editor at SynBioBeta and mentors K-12 students through Schmahl Science Workshops, fostering passion for science from a young age.