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Industrial Biotechnology Shaping Corn Biorefineries of the Future
Vijay Singh,1,2 Joel Stone,3 Jeffrey P. Robert,4 and Sundeep N. Vani5
© 2019 AACC International, Inc.
Bio-based markets, enabled by synthetic biology and increased emphasis on sustainability, are growing in the United States and around the world. Over the last five years, an exponential increase in investments in synthetic biology has been observed. Large amounts of renewable carbon in the form of fermentable sugars will be required to enable the production of next-generation biopolymer, biochemical, biofuel, and food products. In North America, sugars from corn (maize) will be the most abundant carbon source available to drive the industrial biotechnology engine. The demand for renewable carbon will improve stability in agricultural economies and support regional agricultural job creation. Traditional corn processing facilities are responding to this need by retrofitting their processing facilities to produce low-cost sugars or redirecting sugars from shrinking high-fructose corn syrup and dextrose markets to high-growth industrial biotechnology markets. However, there are still challenges that must be overcome to convert this opportunity into commercial reality. To succeed, new product and process development initiatives must meet economic, regulatory, quality, and other requirements within budget and time constraints. Translational research facilities that are specifically intended to accelerate commercialization and reduce the risk of utilizing new technologies will play a crucial role in realizing the opportunities offered by industrial biotechnology.
Growth in Industrial Biotechnology
Industrial biotechnology is growing at a fast pace in the United States and around the world, shaping the biorefineries of the future and the development of biomaterials, renewable chemicals, bio-based ingredients, foods, and agricultural products. Recent estimates by the Biotechnology Innovation Organization put the global economic value of industrial biotechnology at US$355 billion (2). There are many reasons for this tremendous growth in industrial biotechnology (13). For example,
- Sustainability has become a megatrend in consumer products
- Advancements in synthetic biology and metabolic engineering
- Availability of abundant, low-cost carbon required for fermentation
- Bridging of the gap between innovations and commercialization for biorefineries
Sustainability as a Megatrend
Industrial biotechnology is enabling a circular economy with increased use of renewables, production of new materials that reduce waste and have superior functionality, products with better life cycles and improved compostability, and use of materials that have better reuse and upcycling applications at end-of-life (15). Major consumer goods companies are using higher amounts of biopolymers and highlighting the sustainability of their products to market them. Consumers also are demanding greener products, which is creating a market demand for bioproducts. nova-Institute’s new market and trend report estimates that the total production volume of bio-based polymers was 8.0 million tonnes in 2018 and is expected to reach 9.6 million tonnes by 2023 (5). As population growth outpaces food supplies (especially meat products), sustainability in food production systems is becoming increasingly important. Recent trends in plant-based products (e.g., meatless burgers, chicken, eggs, shrimp) are becoming more popular and experiencing explosive growth in the United States. In addition to the United States, meatless markets also are expected to grow in Europe and Asia. With worldwide consumption of meat increasing, by 2050 sustainable meat production in certain parts of the world will become challenging. In 2017, China, in an effort to reduce Chinese meat consumption by 50%, announced a multimillion dollar deal to import lab-grown meat from companies in Israel (4). Water, fossil energy, labor, land, and feed use, as well as emissions and nitrogen run-off, associated with producing plant-based meat products are an order of magnitude lower compared with animal meat products (11).
Advances in Synthetic Biology and Metabolic Engineering
Advances in synthetic biology and metabolic engineering have reduced the cost of developing new bioproducts with complex and novel biosynthetic pathways. The ability to express novel enzymes and construct novel pathways has made it possible to produce a wide variety of bioproducts that previously were not possible or were very expensive to produce.
There have been several key developments over the past 10 years. However, the key game changer has been the developments in synthetic biology that have resulted from CRISPER-Cas9 technology. So, what is CRISPER-Cas9 technology? “CRISPR” is an abbreviation for “clusters of regularly interspaced short palindromic repeats” (6,10). To simplify the discussion, CRISPR-Cas9 is a genome-editing tool. The genomes of various organisms encode series of messages and instructions within their DNA sequences. Genome editing involves changing those sequences and, thereby, changing the messages. This can be done by inserting a cut or break in the DNA and “tricking” the natural DNA repair mechanisms of a cell into introducing desired changes. CRISPR-Cas9 provides a means to do this. The power of this editing tool when coupled with management of big data allows us to predict the changes in chemicals, proteins, or materials produced by an organism. CRISPR-Cas9 has allowed industrial biotechnology companies to accelerate the development of specialized fermentation organisms from years and millions of dollars in investments using traditional mutation development, to months and tens of thousands of dollars in investments using targeted genome editing. This is a defining moment in the transformation of agricultural feedstocks that are serving a growing industry and an indicator of what might be in store for the new world of biorefineries.
Many experts in the industrial microbiology field view synthetic biology and its products as an accelerated growth and expansion of biotechnology progress, similar to the progression experienced since the inception of the information technology (IT) field and its expansion according to Moore’s law. (Moore’s law is the observation made by Intel cofounder Gordon Moore that the number of transistors on a chip doubles every year, while the costs are halved. Moore’s law predicts that this trend will continue into the foreseeable future). Investments made in synthetic biology over the past five years, which approach nearly US$8 billion, serve as an early indicator of the product pipelines that are being developed and clearly shape the opportunities for existing ethanol facilities where fermentable sugars can be diverted to new product fermentations. The most recent data on synthetic biology funding, as presented by SynBioBeta (16), is shown in Figure 1. The rapid pace of further investments is continuing in 2019. All of this indicates there are significant opportunities for expansion of biorefineries throughout the U.S. agricultural economy and, more widely, internationally as agriculture feedstocks are more fully developed to produce fermentable sugars.
Within the innovation window, synthetic biology must be considered a disruptive technology related to the launch of commercial products, and we must keep in mind what this means for the products and industry. Bio-based products will change the original trajectory of traditional production, redirecting production to fermentation-based processes (Fig. 2). Bio-based chemicals and materials can exploit opportunities in the US$450 billion specialty markets (Fig. 3). These markets are quite diverse, with significant segmentation, which greatly reduces market risks. Above and beyond these specialty markets, synthetic biology is targeting the following markets as well: animal health, aquaculture, biomass to sugars, nanocarbon and cellulose, biofibers, food ingredients, lubricants, nutraceuticals, microbiome, biostimulants, enzymes, biopesticides, food proteins, and biofertilizers.
Availability of Abundant, Low-Cost Carbon Required for Fermentation
Based on the continuing investments in synthetic biology and industrial biotechnology, we can confidently predict that there will be significant growth in industrial fermentation over the next decade as products move from lab, to pilot, to demonstration, and, finally, to commercial production. According to a report from the National Academy of Sciences, fermentation and catalytic conversion technologies are going to be a major unit operation that will drive the bioeconomy in the United States and around the world (12). However, to meet the demands of this growing biochemical industry, abundant renewable carbon sources (sugars) are needed at a price point that enables bioproducts to be produced economically. Renewable feedstock, such as cellulosic biomass, is currently being developed for sugar production. Despite intense research and development activities, the production process for extracting sugars from cellulosic biomass remains challenging compared with corn (maize) and other sugar crops due to the recalcitrant structure of cellulosic biomass. Currently, there are only four places around the world where abundant, cost-effective sources of carbon are available: Brazil (cane); Europe (beets and wheat); Southeast Asia (cassava and cane); and the United States (corn) (7). Corn production is expected to expand in the United States, and by 2030, production yields are expected to be 200–300 bu of corn/acre (8), with more corn available for industrial processing.
Major industrial processing of corn is performed by the wet-milling and dry-grind industries. The corn wet-milling industry traditionally has produced corn sugars (i.e., dextrins, glucose, and high-fructose corn syrup) for food and beverage applications, in addition to coproducts for human and animal food products. Growth of the U.S. corn wet-milling industry closely follows the total caloric sweetener production trend (Fig. 4). However, since 1999, total caloric sweetener production has been decreasing in the United States due to lower sugar consumption per capita, and the wet-milling industry has been going through major consolidation. This decrease in sugar consumption in foods has redirected production of more sugars for bioproduct and food protein applications. Recently, interest in production of food proteins to sustain the growing world population, in particular fermentation alternatives to animal proteins, has grown, and meat alternatives have become an increasingly hot market (3).
The U.S. wet-milling industry dominates current domestic sugar production. However, the industry is nearing its maximum capacity for glucose production and other starch-derived oligosaccharides that are predominately sold to the food and industrial manufacturing sectors. The wet-milling industry, which consists of 22 operating facilities in North America, produces a combined estimated total of ~6.8 million metric tons (t) of glucose and fructose per year on a dry basis (db). Because more than 99% of this production is tied up in long-term contracts, the glucose available to the spot market for new or expanding ventures is estimated at only 34,000 t (db)/year (www.mckeany-flavell.com). Although there is the potential for the industry to switch low-margin fructose sales to glucose sales, existing market pricing drivers will limit this reallocation strategy, because wet-mills maximize profits. As a result, the wet-milling industry can command strong commercial industrial glucose pricing, ranging from US$0.18 to 0.30+/lb (db), for free on board (FOB) mill
Currently, the U.S. dry-grind industry produces roughly 15 billion gal of ethanol/year (14). With more than 90% of its capacity installed in the past 15 years, the industry includes more than 200 facilities that are highly integrated to maximize both ethanol production and energy efficiency. Although viewed as ethanol plants, these facilities in reality are designed to create glucose that is subsequently processed by fermentation into ethanol. A typical dry-grind yield is 2.85 gal of anhydrous ethanol/bu of corn, so the ethanol industry is actually processing more than 86 million t of glucose (db)/year—10 times that of the wet-milling industry. Furthermore, the glucose produced can have an estimated market value, based on current net margins at dry-grind plants, ranging from –US$0.02 to +US$0.07/lb (db), for FOB mill (due to the tight commodity pricing of ethanol and its related coproducts). Even though the grain-to-ethanol industry has optimized the process and chemistry used to convert these sugars, the glucose produced cannot be utilized in its typical dry-grind slurry state by the biochemical industry due to its low purity and the presence of organic and inorganic inhibitors.
Recognizing the growth potential of the biochemical industry, the shortage of available glucose in the marketplace to support this growth, and the opportunity to deploy its core competency in grain processing, design, and optimization in the dry-grind industry, Fluid Quip Technologies (FQT) has developed and deployed a unique, patented, commercial-scale Clean Sugar TechnologyTM (CSTTM) system that can be retrofitted to any dry-grind, cereal-processing facility. In addition to other retrofit technologies offered, this technology provides a diversification strategy for the dry-grind industry that allows adopters to move both proteins and carbohydrates into other value-added marketplaces. Through these technologies, FQT has demonstrated that a dry-grind process can produce a net starch price of US$1.45/bu or less, well below the net starch price of US$1.75/bu that is attainable with the current wet-mill process.
A typical flow configuration for a dry-grind ethanol facility, irrespective of the technology provider, is illustrated in Figure 5. The hydrolysis of starches in the cereal grain to glucose and fermentation are performed concurrently in a process known as simultaneous saccharification and fermentation. The novel approach introduced by FQT diverts a slip stream of liquefied mash from the ethanol process to produce clean sugar (9), with resultant side streams reintroduced into the ethanol plant to recover both sugar and nonsugar components (Fig. 6). This technology, in operation since 2016, currently is being used to produce more than 130,000 t of glucose (db)/year at the Green Biologics facility located in Little Falls, MN. Through this project, FQT has demonstrated that, by leveraging the existing “sugar processing infrastructure” in a dry-grind ethanol plant, the potential to produce substantially greater quantities of industrial glucose, refined or unrefined, can be realized. Further, CST can produce sugars at or below US$0.10/lb of unrefined glucose (db), for FOB dry-grind mill. It has also been shown that this same approach can be utilized to produce food-grade glucose (Fig. 7). A similar study conducted by Zhaoqin et al. (18) demonstrated that high-quality sugars can be produced in a dry-grind corn process.
Bridging of the Gap between Innovations and Commercialization for Biorefineries
Earlier in the article we discussed the market potential for bio-based products. The market drivers have aligned very well with advances in synthetic biology, which make it easier to design biosynthetic pathways. Thus, market-driven demand for sustainable products, advances in synthetic biology, and access to less expensive feedstocks have created a great opportunity to produce commercially viable bio-based products at a large scale. However, certain challenges have to be overcome to convert this opportunity into commercial reality. A new product (or a new process to produce an existing product)—“drop-in replacement” or “bioadvantaged”—must meet multiple requirements before it can be successfully commercialized. Product development initiatives must meet these requirements within budget and time constraints. The following are some of the major issues to consider when bringing a new product to market:
- Production economics
- Regulatory requirements
- Quality specifications
- Capital investment (alignment with asset availability and asset utilization)
- Customer application requirements
- Availability of feedstocks, utilities, water, and other consumables
- Intellectual property and technology expertise
Significant investments are required during the product development cycle to satisfy all of the key requirements. Depending on the nature of the products and markets, the level of investment will vary. For example, a new bio-based polymer might require significant customer testing to ensure that the polymer functions well in the end application. Significant quantities of representative product may have to be produced to perform the required testing. For the customer to fully qualify the product for the end application, the process used to produce the sampled product should be as representative of the final process as possible. To produce representative product in sufficiently large quantities for customer trials may require a significant investment in technology development, application development, manufacturing assets, production materials, etc.
Given the large investment often involved during the development cycle, it is a commercial imperative that revenue and profits be realized quickly. Timing is critical because investment returns are sensitive to timing. In addition to investment returns, other factors, such as intellectual property rights with a limited duration, competitive pressure, and changing consumer trends, also create a sense of urgency and influence investment decisions.
A quick review of the development process is helpful to understand the impact of investment decisions on research and development efforts. A typical product development cycle for a biotechnology-based product consists of four phases, which can be summarized as follows:
- Strain Development and/or Enzyme Development Phase—This phase may involve 1) identifying the important enzymatic steps and corresponding genes; 2) synthesizing the target genes; 3) selecting a host; and 4) optimizing gene expression.
- Process Development Phase—This phase may involve 1) developing upstream and downstream processes; 2) manufacturing samples of the target product; 3) quantifying production and capital costs; and 4) collecting data and preparing for regulatory filings and compliance.
- Production Phase—This phase includes construction of the production asset and starting production. It may involve 1) selecting equipment; 2) developing capital estimates; 3) designing and constructing the plant; and 4) startup and production activities.
- Commercialization Phase—This phase includes final customer acceptance of the target product and may involve
1) achieving all product quality metrics; 2) reducing failure rates; 3) achieving target production economics; and 4) achieving full capacity.
All of these phases require commitment of resources. The process development phase is often a critical connection between the science and testing and large-scale implementation. Extensive and diverse assets, as well as expertise, are required to conduct a successful process development effort. Some commonly required types of assets and capabilities include
- Laboratory equipment
- Trained scientists and technicians
- Analytical capabilities
- Pilot plant (or larger scale production equipment)
A large organization usually will have a core set of resources that includes many of these capabilities and provides a strong foundation. In larger organizations, these core resources may also be supplemented, as needed, with project-specific equipment and expertise. Smaller organizations may not have the resources to invest in all of these resources simultaneously. The need for these resources may be critical during the development phase but may diminish once the product is commercialized. In a large organization, there is a pipeline of development work that will continue to utilize these resources, justifying the investment in acquiring them. However, a smaller organization cannot justify acquiring all of these resources knowing that they will be underutilized once the process is commercialized. Efficient resource management is one of the keys to successes. Resource deployment must be both timely and cost-efficient.
Building capabilities in the following areas may provide the necessary balance between reducing costs and capital commitments during process development, while providing scheduling flexibility:
- Develop Robust Process Modeling Tools: Generally, performing rigorous simulations can reduce the need to perform experiments. Experimental work is almost always more expensive and time-consuming compared with in silico development. The petrochemical industry has been relying on process simulation tools to assess different options and identify promising solutions for experimental validation. The set of tools available for bioprocess development are not as extensive. Greater investment in developing fundamental data (e.g., characterizing thermodynamic and kinetic parameters) for important unit operations may reduce development time. Process modeling capability also increases the ability to consistently replicate performance at larger scales without expensive optimization efforts.
- Develop and Exploit High-Throughput, Robotics, and Automation Capabilities: High-throughput automation, robotics, and data analytics have been applied extensively, with tremendous success, in strain development, DNA synthesis, and other laboratory operations. Application of these same techniques in process development is expanding. Fully exploiting these capabilities enables systematic analyses of multiple variables and ultimately speeds up process optimization and reduces resource requirements. Some of these techniques have been discussed elsewhere (17).
- Accelerate Development through Partnerships: Acquiring, installing, and starting up equipment requires significant investments in capital and time. In addition, committing capital resources to acquire all the equipment, particularly at pilot-plant scales or larger, is risky if there is uncertainty about whether the chosen unit operations will be appropriate for the process. Overcommitting capital resources early in the development cycle can cause budget constraints later and may reduce flexibility in trying alternative approaches if the chosen options do not deliver the desired results. Partnering with university-based facilities that are specifically intended to accelerate commercialization is a very good option. The Integrated Bioprocessing Research Laboratory (https://ibrl.aces.illinois.edu) operated by the University of Illinois is one such facility.
Vijay Singh, Ph.D., is a distinguished professor of bioprocessing in the Department of Agricultural and Biological Engineering and director of the Integrated Bioprocessing Research Laboratory (IBRL) at the University of Illinois at Urbana-Champaign. His research is on the development of bioprocessing technologies for corn and biomass to ethanol, advanced biofuels, and food and industrial products. In his role at IBRL, Vijay provides leadership in developing industrial partnerships, bioprocess pilot-scale proof-of-concept activities, and techno-economic analyses to facilitate commercialization of innovative technologies. A Fellow of AACC International, Vijay has been an investigator for research and center grants totaling more than US$140 million and has authored 185 peer-reviewed journal articles. Vijay has received numerous excellence in research and teaching awards from professional societies, academic institutions, and trade organizations. In 2015, he was selected as a University Scholar, the highest honor given to a faculty member at the University of Illinois system-wide. Vijay received his M.S. and Ph.D. degrees in food and bioprocess engineering from the University of Illinois at Urbana-Champaign. LinkedIn: https://www.linkedin.com/in/vijay-singh-6a41316b.
Joel Stone is the president of ConVergInce Advisers, which is focused on delivering “visionary and innovative solutions,” including commercialization assistance for synthetic biology and advanced technology clients in renewable chemicals, biochemicals, biofuels, and agricultural and bio-based ingredients for food, fragrance, and consumer products. Joel is the former president of Green Biologics Inc., where he led the development of the commercial platform of the company in North America for renewable n-butanol and acetone for use in the renewable specialty and performance chemical markets. He has provided executive leadership at several companies, including ASAlliances Biofuels, Osage BioEnergy, Abengoa, Balchem Corporation, Opta Food Ingredients, and Genencor (now Dupont Biosciences). He has provided oversight for complex technologies and chemical processes at both pilot and development scales and commercial scale. Joel holds a B.S. degree in chemical engineering from Virginia Polytechnic University and an M.S. degree in chemical and biochemical engineering from the University of Pennsylvania. He has served and currently serves on the Board of Green Biologics, Fermentum, Biorenewable Deployment Consortium, and Business Climate Leaders. LinkedIn: https://www.linkedin.com/in/joelastone.
Jeffrey P. Robert provides a unique and diverse perspective to business, technology, operations, and commercialization. Jeff is an accomplished business executive and entrepreneur who has created multiple businesses and innovative technologies and numerous operational advancements in the food, biofuel, and biochemical industries. As president of Rendezvous Consulting, Jeff has served in several technical advisory and leadership roles over the past decade. He has assisted several leading cellulosic ethanol, biochemical, and engineering service providers, supporting their modeling, scale-up design engineering, commercialization, and execution platforms in North America, South America, and Europe. He serves on the technical advisory board for a multinational food corporation, acts as a lead technical investigator and business advisor for companies seeking value-added and optimization solutions for their operations to enhance business profitability, and provides an interface for international business plan execution. Jeff holds a B.S. degree in chemical engineering from the University of Wisconsin-Madison. He holds patents and patent-pending applications in the area of new product and process development, as well as membrane filtration technology. LinkedIn: https://www.linkedin.com/in/jeffrey-robert-aa369a7.
Sundeep N. Vani, Ph.D., consulting practice, commercialization of bio-based products, is an experienced executive with more than 20 years of experience and has expertise in product commercialization, including technology, operations, and business-related activities. He has extensive knowledge of bio-based products (amino acids, organic acids, biopolymers, probiotics, enzymes, animal-free proteins, carotenoids, and others), processes (pretreatment, fermentation, biocatalysis, and product purification), and markets (specialty chemicals, food ingredients, feed ingredients, biofuels, and others). He also has conducted due diligence to support investment decisions and has served on steering committees and advisory boards providing strategic and tactical oversight. Sundeep holds a Ph.D. degree in chemical engineering from Rice University. He worked for two companies before serving in roles of increasing responsibility at Archer Daniels Midland Company. Sundeep also earned an MBA from Northwestern University. Currently, he is advising diverse clients, including venture capital funds, early-stage synthetic biology companies, and large multinational corporations. LinkedIn: https://www.linkedin.com/in/sundeep-vani-8541133.
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