Reinventing Manufacturing Using Metabolic Engineering: A Chat with Manus Bio’s Christine Santos

This content is provided by Manus Bio and reflects their views, opinions, and insights.

Metabolic engineering and industrial biotechnology have the potential to disrupt the current chemical and material manufacturing processes to make them more sustainable and economical. I had a chance to talk with Dr. Christine Santos, the Chief Technology Officer of Manus Bio, who works to develop and scale-up biomanufactuing platforms with the goal of commercially producing natural products. We discussed the possibilities that metabolic engineering can unlock, as well as the challenges that the field needs to overcome to get there. 

You can learn more about Manus Bio’s work at the Metabolic Engineering 14 (ME14) Conference, where CEO Aji Parayil will be speaking about reinventing chemical manufacturing using biotechnology. 

ME14 attendees can also receive a free sample of Manus’ NutraSweet Natural^TM, a superior-tasting stevia sweetener. If you are a ME14 attendee, sign up here to receive a sample from Manus.

What are some of the most exciting developments in metabolic engineering that you have seen in the past year or two?

There has been a growing realization across many industries that sustainable and economical sourcing of both existing and novel chemicals and materials requires a new approach – and that metabolic engineering and industrial biotechnology are well-positioned to provide a solution for this problem. It has therefore been really exciting to work with more and more traditional chemical, materials, or extraction companies in developing their long-term vision for incorporating and eventually transitioning to bio-based products within their portfolio. These sizeable market opportunities have also piqued interest among the investment community, leading to significant capital going into metabolic engineering and synthetic biology companies in the last couple years – to the tune of $8B last year and up to $36B predicted for this year.

Despite all this public interest, I think it is important to recognize that truly disruptive technologies like metabolic engineering typically take decades to reach the maturity and scale needed for broad adoption into society, and we are just starting to enter that phase as a community. It has been very encouraging to see a handful of successful launches into the market, including a few of our own products at Manus, but we need to be patient and diligent as an industry to realize this technology’s full potential.

How does Manus apply metabolic engineering to commercial applications?

Metabolic engineering is an absolutely integral part of strain and process development, as all cell factory design requires complete rewiring and retuning of the cell’s metabolism to reach the metrics (titer, rate, yield) needed for commercial production. Our approach at Manus has been to merge two different concepts: 1) universal chassis that have been engineered to make high levels of the main precursors to a variety of classes of chemicals and 2) a “Multivariate Modular Metabolic Engineering” (MMME) framework to efficiently design and optimize complex biosynthetic pathways to specific products. Some of these target molecules require an additional 10–15 heterologous biosynthetic steps from the cell’s native metabolic precursors, so the simplification and efficiency afforded by taking this combined approach is critical for developing commercial processes.  

One point that I think bears mentioning though is that biomanufacturing is truly an interdisciplinary endeavor. Metabolic engineers must work hand in hand with many other scientific and engineering disciplines to translate this technology into a commercial reality. Protein engineers with deep knowledge on enzyme mechanism, structure, and dynamics are critical for being able to improve the in vivo functional performance of these biocatalysts; systems biologists and biochemists enable better understanding and predictability of cellular behavior and processes by leveraging transcriptomics, metabolomics, and proteomics technologies; fermentation and downstream process development engineers must characterize and understand the strain’s idiosyncrasies to develop a robust process for production and recovery that can be operated economically at scale; mechanical, electrical, and process control engineers are needed to design, build, and operate the large-scale manufacturing facilities for generating products. All these disciplines must be seamlessly integrated to be successful as an industry.

One challenge of metabolic engineering is scaling up the reactions and processes to a commercial scale. How do you see companies in the metabolic engineering community overcoming this challenge in the coming years?

Unfortunately, access to facilities for both piloting and large-scale production is going to be a bottleneck in the future for the community. The handful of piloting and production facilities that have been used more commonly in North America and Europe have seen demand significantly outstrip their capacities. However, our industry and the U.S. government are realizing this and beginning to invest more in the capital infrastructure needed to be able to bridge that gap to commercial scale. For example, last year, the U.S. Department of Defense (DOD) awarded an $87M seven-year contract to BioIndustrial Manufacturing and Design Ecosystem (BioMADE) with the goal of building out biomanufacturing capabilities and resources in the U.S. A few companies have invested themselves or partnered with other larger players to start building out dedicated facilities for some products, although this requires not only significant capital investment but also a solid understanding of the market take-up for what are potentially new products.

At Manus, building out manufacturing capabilities has been a core part of our strategy (in fact, the name “Manus” is the Latin root for the word manufacturing) and so we made a strategic decision in 2018 to acquire a large manufacturing asset in Augusta, Georgia. Access to this fully modular piloting, scale-up and manufacturing facility has allowed us to test our strains and process in earlier stages of product development and has significantly accelerated commercialization of our products.

Can you tell us more about the process for Manus’ sweetener, which Metabolic Engineering 14 conference attendees can receive a free sample of?

Manus has applied metabolic engineering and other technologies to develop a process for making the rarest and best-tasting parts of the stevia plant as a natural non-caloric sweetener. Most stevia sweeteners on the market today are derived from leaf extracts which contain high percentages of a steviol glycoside called Rebaudioside A, which has sweetening properties but also a very undesirable bitter and metallic off-taste. Our process enables the production of Rebaudioside M, a superior-tasting steviol glycoside which has previously been inaccessible in large quantities due to its rarity within the plant. We are excited to be able to offer this innovative new ingredient, both to food and beverage companies as well as direct to consumers through our tabletop sweetener NutraSweet Natural^TM (https://nutrasweetnatural.com/). I encourage all ME14 attendees to stop by Manus' exhibit booth to sign up for a sample or to purchase the product directly from our website or through Amazon. It is not only a great-tasting product but also a wonderful example of the power and impact that metabolic engineering can have on driving towards a healthier and sustainable future.

 Disclosure: This content is provided by Manus Bio and reflects their views, opinions, and insights.