New BioMADE Bioreactor Innovation Projects Aim to Supercharge the Future of Large-Scale Biomanufacturing

BioMADE is excited to announce five new projects that focus on developing more efficient, lower-cost, flexible, and re-deployable bioreactors to advance the U.S. bioeconomy and biomanufacturing goals. Project teams led by members Capra Biosciences, Amyris, Geno, and two teams from Iowa State University propose technological innovations in bioreactor hardware, software, sensors, modeling, and automation to make bio-based products more efficiently at commercial scales. These projects were funded through a special BioMADE Project Call on advancing bioreactor design and development thanks to support from Schmidt Futures.  

Scaling the U.S. Bioeconomy 

Both the BioMADE Technical Committee and the Schmidt Futures Task Force on Synthetic Biology and the Bioeconomy identified bioreactor innovation as a key priority area for scaling up the production of bio-based chemicals, materials, and biomolecules. Eric Schmidt addressed the BioMADE community at BioMADE’s inaugural Member Meeting in June 2022. In his address, he introduced the project and laid out the rationale for why bioreactor innovation is needed:  

“Synthetic biology can help solve some of the hardest problems we face today,” thinks Schmidt. “But to harness biology’s incredible ability to produce things at a massive scale, we first need to overcome some important problems. We are interested in figuring out how to repurpose sustainable biomass and how to overcome engineering constraints in bioreactors – because if you don’t solve those two problems, you will never get to scale.” 

Schmidt Futures estimates the value of the U.S. bioeconomy at nearly $1 trillion, with the potential to reach $4-30 trillion over the next 10 to 20 years. Progress in genome editing technologies, understanding of biology, artificial intelligence, automation, and miniaturization are all contributing to this potential. Yet, very little work has been invested in bioreactor innovation. As a result, this technology has largely remained unchanged over the past few decades:  

“If you look at fermentation, as the backbone of biomanufacturing, when we're basically using the same technologies as 20 years ago,” says Mary Maxon, Executive Director of BioFutures at Schmidt Futures, who is developing and co-leading the Bioeconomy Program. “The opportunity to use biological systems to advance manufacturing in the U.S. is largely left to industry, and industry is largely focused on using what's available. So that's why we thought this is a great opportunity to drive impact.” 

Challenges and Opportunities 

Bioreactor design is one of the biggest bottlenecks in biomanufacturing today. Current large-scale bioreactors are not portable, they require large amounts of inputs and produce a lot of waste, are difficult to sterilize and maintain aseptic, expensive to operate, and do not provide a lot of insights about the process. Standard bioreactor design is largely based on technologies used in the chemical industry, which does not account for the complex dynamics of microbial fermentation or downstream processes such as separation. These are just some of the issues that need to be addressed.  

One of the new BioMADE projects proposes a continuous bioreactor that integrates product extraction and separation steps. "Development of a Continuous Taylor Vortex Fermentor-Extractor-Separator” led by Prof. Dennis Vigil at Iowa State University aims to solve multiple problems, including improving the mixing and flow of the media and re-purposing the rotating motion of the bioreactor cylinders to serve as a centrifuge.  

“One of the questions posed in the project call was ‘how can we combine processing steps so that less equipment is needed?’” Vigil notes. “What we have proposed is not just a novel bioreactor, it's a bioreactor-separator. If we can demonstrate that [it works], it could be revolutionary.” 

Another continuous flow bioreactor design project is led by Capra Biosciences in collaboration with Boston University and Next Rung Technology. The three organizations are partnering to address the various aspects of a bioreactor design for biofilm-forming organisms, including the issues of automation, next-gen sensing, and separation methods. Capra’s biofilm-forming organism enables their specialized bioreactor with continuous product synthesis and direct solvent extraction, which is designed to make chemical synthesis more cost-effective and sustainable than conventional fermentation infrastructure. 

“Our biofilms have a lot of advantages in enabling continuous flow and manufacturing,” says Andrew Magyar, co-founder of Capra Biosciences. “But one of the challenges is we can't go buy an off-the-shelf system that allows us to do experiments at a small scale and then scale up to our bioreactor. By working with Boston University, we're testing an automated culture system that allows us to make predictions for scaling from milliliter scale to a 30-liter or larger scale.” 

This bioreactor is modular, which makes scaling production much easier and helps prevent issues like contamination. Capra’s collaborators at Boston University are developing automated culture platforms, as well as next-gen wireless sensors to allow monitoring and control of the bioreactor, while Next Rung is helping Capra build their first pilot plant. Capra’s technology, which is capable of using waste feedstocks, answers many of the current challenges of adopting sustainable biomanufacturing practices:  

“Creating a circular economy is necessary for us to live sustainably on the planet,” said Capra’s co-founder and CEO Elizabeth Onderko. “If you have a system like ours that's capable of using low-cost, widely available feedstocks, it can be really powerful from both a climate and economic perspective.” 

Building on Experience 

Many of the BioMADE members are companies that have already demonstrated the production of bio-based chemicals at commercial scales. Two of them, Geno and Amyris, are participating in bioreactor innovation projects to further improve the efficiency, scalability, and predictability of commercial fermentation. Project MONDE, led by Amyris and Sudhin Biopharma, aims to integrate new technology for removing inhibitory fermentation products at a pilot plant scale. This is a follow-up to another project funded through BioMADE which has shown this method can be successfully applied at lab-scale:  

“Certain types of products like alcohols or monoterpenes are difficult to produce at a level that would be commercially relevant due to their inhibitory effect on the organism,” said Paul Hill, Senior VP of Process Development & Engineering and the project lead at Amyris. “We have demonstrated we can remove those compounds using oil-water separation, but doing so aseptically at a relevant scale is challenging. Project MONDE, in collaboration with Sudhin Biopharma, aims to address that limitation.” 

In addition to demonstrating the scalability of the process, the project includes an economic analysis of the projected implementation costs for different types of products used in fuels, commodities, food and beverage, and personal care applications.  

Geno is similarly working on scaling up fermentation processes. Through the bioreactor innovation project, they are developing and validating models to predict the performance of oil-producing fermentations at a demo scale based on laboratory results:    

“Fossil fuels are sourced to make many different products, from apparel to carpet and car parts. And, the rainforest is being burned down for the production of palm oil that goes into a variety of products, such as home cleaners and shampoos,” says Stefan de Kok, Director of Fermentation at Geno. “Using engineered microbes and fermentation technology can provide a sustainable alternative for these products.”   

“An important aspect that this project specifically addresses is scale-up. We do all the research and development in a one-liter reactor but ultimately, these molecules will be produced in reactors that are several hundred thousand liters. And the question is, how do we generate lab results that translate well to a larger scale?”   

To address this issue, Geno models the pressure and concentration gradients present in large-scale bioreactors and then mimics those conditions in lab reactors, collecting data and improving the models along the way: “This project is intended to help ensure that scale-up is predictable, with no surprises. We have successfully scaled up several types of fermentations, and this project builds a foundation to scale up oil-producing fermentations predictably, as well,” says de Kok.   

Another project that is focused on modeling the processes inside the bioreactor is led by Prof. Nigel Reuel from Iowa State University in collaboration with Novozymes. The team is developing a generalizable machine-learning framework for the optimization and control of bioreactors. Focused on enzyme production, the project has two components: the application of new product sensors capable of measuring enzyme activity continuously and directly from the reactor, as well as the development of open-source software for bioreactor monitoring that will be shared with BioMADE members.  

This project also integrates an educational component by funding two graduate trainees and providing opportunities for them to work on real-world applications: “I push my Ph.D. students to have some sort of external experience,” says Reuel. “Almost all of them have done a semester or summer working at a company. So, when they go out to interview for jobs or to create their own company, they know what to expect and how to do it.” 

Looking Forward

These projects are part of BioMADE’s ongoing efforts to strengthen domestic biomanufacturing capacity, which includes funding research, fostering partnerships, disseminating knowledge, and educating the future biomanufacturing workforce. BioMADE is also committed to incorporating safety, security, sustainability, and social responsibility (4S) into its projects. All of the selected projects address those issues in addition to proposing a unique approach to the technical challenges of bioreactor innovation:  

“We are excited about the different approaches each of the teams took to bioreactor innovation,” said Penny Norquist, BioMADE Senior Technology Program Manager. “Each project addresses some aspect of bioreactor innovation, from design to monitoring and modeling what's happening inside the reactor to separation techniques.” 

By harnessing the power of biology, BioMADE and its members are creating more robust and resilient supply chains, making the U.S. more self-sufficient, re-shoring manufacturing jobs, and producing more environmentally sustainable products without relying on traditional petroleum sources. BioMADE is also building a diverse and globally competitive STEM workforce to ensure American workers are prepared and ready to fill new jobs within this rapidly growing industry.  

“Our goal is to create a dynamic ecosystem that can solve some of the challenges of bio-industrial manufacturing and create resilient supply chains here domestically,” said Melanie Tomczak, BioMADE Chief Technology Officer. Tomczak thinks that the partnership with Schmidt future can bring more visibility to the industry as well and generate an impact that ripples across the nation.  

“What I imagine as the future is that we will have a diverse workforce of people of all career levels and that it will being jobs to the parts of the U.S. that have not benefited from the innovation happening near the coasts,” hopes Mary Maxon.  “We can give new jobs to people who never imagined they would have biomanufacturing roles, foster a diverse workforce, and bring investment to rural communities.”