Frontier Report: The U.S. Bioeconomy: Charting a Course for a Flexible and Competitive Future

Editor's Note

The bioeconomy is an economic activity driven by research and innovation in life sciences and biotechnology aimed at creating useful products in a wide range of sectors such as clean energy, agriculture, industry and health, thereby creating jobs, combating climate change, and reducing dependence on fossil fuels. At present, the bioeconomy has begun to gradually replace the energy economy and become an important area of national power competition, and both China and the United States have listed it as a strategic and forward-looking key direction to promote.

Schmidt Futures, a think tank sponsored by Eric Schmidt, chairman of the National Security Council's Artificial Intelligence and Defense Innovation Committee and former CEO of Google, recently released the report "The American Bioeconomy: Charting a Course for a Flexible and Competitive Future." The report points to the importance of U.S. development-related areas and recommends that the U.S. make more strategic investments and build an easily accessible national computing and database infrastructure to guide the $4 trillion global bioeconomy into the future.

The contents of the report also have important reference value for the mainland's development of biotechnology and bioeconomy. To this end, Core Airlines has compiled parts of the report for the benefit of readers.

Project Introduction

To drive the next wave of innovation in synthetic biology and bioeconomy, Schmidt Future established the Synthetic Biology and Bioeconomy Working Group in October 2021 as part of a program to promote transformative bio-oriented and bio-enabled applications in clean energy, industry, agriculture, health and more. The working group includes content experts from academic disciplines such as physics, ethics, synthetic biology, venture capitalists and industry leaders from small and large companies, and leaders from the Biotechnology Alliance.

Given the breadth of topics discussed in relation to bioeconomy, this mid-term report focuses on identifying "research needs when driving biology-based production" and assessing infrastructure needs to support the bioeconomy of the United States. A follow-up strategy paper planned for spring 2022 will provide recommendations on other topics such as talent/people development, policy modernization, and catalytic actions to stimulate innovation. Schmidt Future is considering its strategy paper for 2022 and welcomes information on this interim report as well as ideas for stakeholder meetings. All information should be submitted to the project co-leaders listed below.

In preparation of this interim report, members of the Working Group met regularly to discuss various topics and developed two new research products to inform the recommendations made. The information gathered for this report includes interviews with more than 50 experts, a literature review, and information from conferences and webinars. Schmidt Future is grateful to the many people who have contributed to these efforts, as well as to the members of the working group who have devoted so much time to this project.

Executive Summary

In the nearly 50 years since the first genetic engineering experiment began, the United States has become the world's biotechnology powerhouse, and its biology-based economy, or bioeconomy, generated nearly $960 billion in economic activity in 2016, about 5 percent of U.S. GDP, with more than half of total economic activity coming from outside biomedical fields, including agricultural and industrial biotechnology. In the next two decades or less, a mature bioeconomy will have the potential to transform production processes to manufacture the products of modern society using renewable biomass energy instead of oil. In this way, it will be possible to reduce the country's dependence on fossil fuels, revive manufacturing and employment throughout the United States, build more resilient supply chains, improve national health, and make a significant contribution to the goal of "creating a net-zero greenhouse gas economy." However, decentralized leadership, insufficient talent development, insufficient investment in basic research and bioprocess infrastructure development, and international competition put the United States at risk of losing its world leadership and squandering entrepreneurial momentum and capital market benefits in trying to expand the bioeconomy. Without concrete measures to address these issues, the economy and security of the country, the health of its citizens, and the opportunity for the country to move toward a net-zero economy to create high-income jobs and keep them at home will all be at risk.

Schmidt Future — Eric and Wendy Schmidt's philanthropic initiative — formed a working group to chart a path to the promise of platform technologies such as synthetic biology and artificial intelligence to help achieve the near-term goal of a "4 trillion global bioeconomy." The working group carefully considered the obstacles, focusing on enabling the large-scale production of exciting bioeconomical products that were ready to go out of the lab, thus finding opportunities to translate basic scientific research into products available to the masses. Such products include:

• A new generation of plastics that can degrade into harmless chemicals in seawater and soil;
• Carbon-neutral cement produced by bioprocessing;
• Alternative food protein sources that use less water and land and produce fewer greenhouse gas emissions;
• plants adapted to climate change, including salt- and drought-tolerant crops;
• Its production of textiles and dyes that significantly reduces CO2 emissions and reduces toxic waste;
• Soil microorganisms that reduce fertilizer use, improve soil health, and remove carbon dioxide from the atmosphere.

This report from Schmidt Future makes recommendations for public and private action, divided into two broad categories: basic science and technology challenges, and expanding capacity-based bioproduction infrastructure. The emergence of these categories is based on the fact that most basic life science research in the United States is currently curiosity and discovery-oriented, rather than application-oriented, which creates many "non-academic" challenges that limit the ability to achieve biological production goals, and these challenges continue to be under-thoroughly researched and fully developed in the United States. Moreover, as other countries are working to address these challenges, and U.S. companies are using their overseas technologies to produce and commercialize, if this continues, it will produce the same "innovate here, produce elsewhere" outcomes that have caused too much harm to U.S. manufacturing and manufacturing employees.

A brief description of the recommendations

1. The U.S. government should commit to establishing and funding a five-year, $600 million Bioproduction Science Initiative (BSI) to maintain U.S. global leadership in the biosciences and expand capacity. The Initiative has increased budgets and allocations to key scientific institutions responsible for promoting the development of basic science and technology related to contemporary and future bioproduction, with the main objective of addressing some of the unmet research needs that hinder the transformation of innovative technologies.

• The National Science Foundation (NSF) should act as the lead agency for BSI to establish two regional innovation accelerators (RIAs) focused on bioproduction each year;

• RIA should establish new partnerships with relevant federal scientific agencies to build on existing expertise and leverage early-stage investments to achieve accelerated research coordination.

2. The U.S. government should invest $1.2 billion over two years to build a broad and flexible bioproduction infrastructure (bioproduction capable of processing multiple raw materials with multiple microorganisms and producing multiple products on multiple scales) in order to expand domestic bioproductive capacity in a fair and strategic manner. More financial support is needed in the future to maintain and sustain these investments.

• MoFCOM shall, on the basis of the work of this Working Group, comprehensively evaluate existing facilities and functions in order to identify and seize opportunities to achieve an appropriate and equitable layout of future facilities;
• A network of 10-15 new bioproduction facilities and refurbished bioproduction facilities, coupled with incentives for early technology development, will accelerate the transition from laboratory technology to commercial applications;
• The Department of Commerce should explore other fiscal incentives (e.g., those mentioned in the CHIPS Act) to fund small and large companies to meet their infrastructure needs.

3. To maintain global competitiveness, the U.S. government should establish and maintain creative public-private partnerships with the goal of "reducing the time required to successfully scale new products from years to months."

• The Department of Commerce should incentivize companies with deep AI expertise to partner with companies with biomanufacturing facilities to provide services, facilities and expertise to innovators.

Provide public and private financing opportunities to advance the U.S. circular bio economy and maintain U.S. biotechnology competitiveness

Interim report from the Schmidt Future Group's Bioeconomy Working Group

In the nearly 50 years since Herbert Boyer and Stanley Cohen first conducted genetic engineering experiments, the United States has become the world's biotechnology powerhouse, generating a bio-based economy (i.e., bioeconomy) that generated nearly $960 billion worth of economic activity in 2016 alone, or about 5 percent of U.S. GDP, fostering the growth of private enterprises and a thriving startup ecosystem. But fragmented leadership, inadequate talent development, inadequate investment in basic research and bioprocess infrastructure development, and international competition put the United States at risk of losing its world leader. Without concrete measures to address these issues, the economy and security of the country, the health of its citizens, and the opportunity for the country to move toward a net-zero economy to create high-income jobs and keep them at home will all be at risk.

Net zero refers to the balance between a country's greenhouse gas production and the amount of greenhouse gases that the country has removed from the atmosphere through innovation. When the amount we increase is not greater than the amount of clearance, it is considered to have reached net zero.

In the United States, with scientific and engineering knowledge bases, commercial and venture capital interests, abundant renewable raw materials, a vibrant workforce, and innovations to address the risks of climate change, more and more consumers are demanding and willing to buy products that are less harmful to the environment and other resource-based products at higher prices, and are working with the whole nation to develop the bioeconomy far beyond today's scale. In fact, by using and harnessing transformative expertise in the fundamental components that make up life, we can drive a global shift from using petroleum products and other non-renewable materials to provide momentum for economic activity to using renewable biomass resources to drive economic activity. If the state takes advantage of this opportunity and its many advantages, especially its global leadership in genetic engineering, molecular biology and biotechnology, as well as its strong position in the field of artificial intelligence, we will:

• Enabling countries to meet the goal of establishing net zero greenhouse gas emissions by 2050;
• Building a healthier, more sustainable nation and planet;
• Addressing food security and water security issues;
• Reduce the country's dependence on foreign resources, reduce the trade deficit, and increase and strengthen the resilience of the national supply chain;
• Revitalize urban and rural economies and create economic opportunities for marginalized communities;
• Occupying the largest share of the estimated $4 trillion global industry that will affect the cause and well-being of nearly all of humanity and enabling the U.S. bioeconomy to lead history's Fourth Industrial Revolution, a revolution as important as the invention of the steam engine, the era of science and mass production, and the rise of digital technology.

The transition from an oil economy to a bioeconomy is not wishful thinking, nor is it insurmountable to reduce ecological impacts and increase economic opportunities. Instead, the scientific community, along with entrepreneurs, has come to a deliberate consensus that the bioeconomy offers an important alternative to combating climate change, while also strengthening and growing the U.S. economy. In fact, the U.S. government has invested more than $5 billion over the past 15 years to support bioeconomy research, and the U.S. Department of Energy (DOE) estimates that the U.S. has the ability to sustainably produce more than 1.3 billion tons of renewable biomass per year — without compromising food, animal feed supply and export needs, while transitioning to low-carbon inputs to agriculture and forestry that promote soil health. Through the combined efforts of the federal government, academia and the private sector, the transition to the bioeconomy will present the following potential:

• Create 1.1 million well-paid and intellectually satisfying jobs;
• Prevent $260 billion of annual economic activity from flowing offshore;
• Promote prosperity in rural areas, cities and underserved and marginalized communities throughout the country through the use of locally produced biomass for regional bioproduction;
• Replace transport fuels that may be required for long-haul air travel and shipping, even after electrification of the national transport sector;
• Produce chemicals and biological products using renewable biomass instead of traditional chemical manufacturing and produce entirely new materials that can only be economically produced by nature;
• Creating a reliable, economical and resilient domestic supply chain for the production and distribution of all bio-based products;
• Develop large-scale, low-energy DNA-based data stores to better capture data generated by the rapidly growing human activity;
• Increase the nutritional value of food and improve soil health while reducing agricultural greenhouse gas emissions, nitrogen runoff and pesticide use;
• Make more efficient use of marshlands and forests and improve their capacity to hold carbon and water;
• breeding salt-tolerant, drought-tolerant and disease-resistant crops to improve agricultural adaptability;
• and reduce U.S. carbon dioxide emissions by 450 million tons a year, or nearly 10 percent or more of the nation's carbon dioxide emissions, while exploring the possibility of developing bioprocesses that remove carbon dioxide from the atmosphere.

Moreover, given the creativity of researchers in the public and private sectors, a biology-based economy, with its ability to rely on nature for chemical processes that humans have not yet mastered on a large scale, may produce entirely new materials and production processes, as petrochemical-based economies do. In fact, synthetic organic chemistry carried out by humans has reached its possible limits, and nature has been able to expand the range of available chemicals and materials. Bioeconomical products available today that are less environmentally damaging and less wasteful of valuable resources include:

• Plant-based meat substitutes with a much smaller environmental footprint;
• Production of textiles, dyes, carpets and furniture that reduce CO2 emissions and energy use;
• Synthetic leather made of fungi;
• soil microorganisms that reduce fertilizer use, improve soil health and remove carbon dioxide from the atmosphere;
• Cosmetics and personal care products made from sustainable bioproduction chemicals with low greenhouse gas emissions and do not rely on animal raw materials;
• A new generation of plastics that can degrade into harmless chemicals in seawater and soil;
• Enzymes used in traditional industries such as pulp and paper bleaching, textile processing and food processing to increase efficiency and reduce energy use;
• Bio-produced cement;
• Sustainable fish feed made from methane;
• Biodegradable and compostable plastic containers whose production can reduce greenhouse gases by 200%;
• High-performance biodegradable lubricants and greases;
• Polyurethane foams from seaweed oil left over from the omega-3 fatty acid production process, as well as enzymes specially formulated to be able to wash clothes in cold water.

At the same time, achieving this transition will not be easy and will not be less expensive. Based on the advice of a working group of experts with a wide range of interests and expertise, the interim report provides a roadmap that countries can follow that will enable the United States to maintain its global dominance in harnessing the modern molecular biology revolution and build a fair, vibrant, and sustainable circular bioeconomy that will bring many benefits to the economy, society, the environment, human health, and national security in the coming decades. Schmidt Future will release a more comprehensive plan in March 2022 to drive growth in the U.S. bioeconomy. This interim report focuses on steps to address basic scientific and technological research needs and build strong national end-to-end biocapacity capacities.

Before delving into the steps that the core of our debate and the state need to take, the terms "bioeconomy", "circular bioeconomy" and "bioproduction" need to be defined. For the purposes of this report, we cite the definition of "bioeconomy" developed by the National College of Science, Engineering, and Medicine in its 2020 report, Protecting the Bioeconomy:

"The U.S. bioeconomy is an economic activity driven by research and innovation in life sciences and biotechnology, driven by technological advances in engineering, computing, and information science."

This report draws on several sources of information on our definition of the circular bioeconomy:

The circular bioeconomy is an economic model that abandons the traditional linear economic model of "acquisition-manufacturing-consumption-disposal" and instead harnesses the power of biotechnology, bioproduction design, and advanced analytical and information technology to create processes that achieve sustainable development and regenerative economic cycles. In this cycle, waste products, as inputs to create high-value products and materials, are used and reused for as long as possible, without consuming limited resources or generating waste discharged into the atmosphere, landfills or rivers, lakes and oceans.

Finally, while some reports use the term "biomanufacturing", the term "bioproduction" used in this report is more forward-looking and covers the various industrial and agricultural processes used by commercial entities to manufacture their products:

Bioproduction refers to the use of biological systems, including plants, microbial communities, single living cells and/or partial living cells (called cell-free systems), using biomass feedstocks and carbon dioxide from a wide range of economic sectors such as health, nutrition, agriculture, industrial applications, etc., to produce important commercial products.

Note that this report does not directly focus on how to address the needs of the biopharmaceutical and biomedical sectors in the bioeconomy, although the part of the investment in bioproduction basic research outlined later may also benefit the biopharmaceutical and biomedical sectors, just as biomedical research produces genetic tools and discoveries that drive other areas of the bioeconomy. These areas are heavily funded by governments and the private sector, and significant infrastructure has been installed that differs from non-biomedical applications, among other things, given manufacturing practices and regulatory norms. The fact that biomedical science's leadership in the bioeconomy is in part a byproduct of its continued investment suggests that broader investment in non-medical bioproduct can drive faster growth in the bioeconomy.

Go beyond biofuels and renewable energy

Most media coverage of the country's efforts to reduce greenhouse gas emissions and achieve a net-zero economy has focused on renewable energy solutions, such as electrification in the transportation sector. Of course, renewables, combined with improved energy efficiency, will certainly play an important role in achieving net zero emissions, but the truth is that replacing fossil fuels with renewables will only solve 55 percent of the nation's carbon emissions. Solving the country's other 45 percent carbon footprint will require a change in the way we manufacture consumer and industrial products and the way we grow food, which provides an opportunity for the bioeconomy to thrive.

The key to this opportunity is for about 96 percent of U.S.-made products to use bio-based chemicals as ingredients. In fact, this shift has begun to occur, with some bio-based chemicals already outpacing petrochemicals in several categories, generating at least $125 billion in output each year, between 17 and 25 percent of U.S. fine chemical revenues. The U.S. Department of Agriculture's (USDA) BioPreferred program has identified commercial production of approximately 20,000 bio-based products.

One advantage of chemical bioproduction is the cost of building bioproduction facilities, which are similar to breweries in many ways with current technology. For example, the cost of a bioproduction facility with current technology ranges from $100,000 to $200 million, depending on its size, complexity, and ability to handle multiple production processes. The relatively low cost of a bioproduction facility means that its return on capital is quite attractive to capital markets. Experts consulting for this report also expect relatively low operating costs for bioproduction facilities.

In addition, due to the different properties of biomass and the characteristics of its localized production, the most practical and economical way to establish a biomass chemical industry is to set up biomass processing facilities close to the supply of its raw materials. For example, a bio-treatment facility could be located near a municipal waste treatment facility, thereby converting waste into chemicals, or, as a U.S. company is doing, setting up a bio-production facility near a steel mill in China and using its industrial emissions as feedstock for bioproduction. The joint allocation of bioprocessing facilities and their biomass feedstocks will achieve economic growth across the country and achieve policy goals to revitalize the economies of rural communities, as well as help those who are now or once dependent on fossil fuel production and those who are struggling with unemployment in traditional manufacturing. In order to adapt to the different properties of biomass produced regionally, we need to conduct basic research on production process control. Sending biomass to regional processing centers requires innovation in logistics.

Why now?

The circular bioeconomy will certainly play a key role in achieving the goal of a net zero economy by 2050, in addition to another strong reason to support national investment in the development of the circular bioeconomy: international competition and the risk of missing out on opportunities to revitalize U.S. manufacturing. For decades, the United States has pursued a "innovate here, produce there" model, rather than a "innovate here, produce here" model, which is based on the United States' comparative advantage in innovation over other countries, and it has thus become a manufacturing power and the richest economy in the world. The "innovate here, produce there" model has deprived countries of the opportunity to take full advantage of the electronics revolution and the explosive growth of photovoltaic deployments, both of which are the result of U.S. innovations that have benefited manufacturers in China, Japan and South Korea in large part because of low labor costs. At least some manufacturers will benefit. But this labor cost issue is not expected to be a key issue for bioproduction. The result of this model is a loss of manufacturing capacity, jobs and economic benefits, as well as a supply chain disruption in 2020 that led to a spike in inflation in 2021 and cost U.S. businesses hundreds of millions of dollars.

Today, when it comes to bioproduction, the United States is in danger of repeating the mistakes of the past. Due to underinvestment in process development research, process engineering, bioproduction infrastructure, and workforce development, many U.S. innovators in bioproduction have had to rely on pilot and bioproduction facilities in Mexico and Europe, giving way to European talent to develop large-scale bioproduction processes and export their intellectual property to make products, as their predecessors in the electronics and photovoltaic sectors did. In addition, if demand for fuel ethanol and high-fructose corn syrup declines, the existing bioeconomy developed around corn processing in the Midwest could be at risk. Therefore, harnessing existing biomass resources to produce innovative products with sustainable market demands can help ensure sustained growth in the bioeconomy of the Midwest.

In addition, international competitors have made it clear that they will dominate the global arena in the 21st century with biotechnology and are investing in the implementation of related long-term strategic objectives. India and China, in particular, have made it clear that they intend to become the dominant global force by developing their domestic economies and mastering biotechnology. To avoid falling behind other countries and losing america's current strengths in biotechnology and molecular biology, the United States must begin planning and implementing on the timelines of multiple ten-year programs used by our competitors.

Meanwhile, dozens of recent reports, hearings, and developing bills suggest that the time is right to use the current momentum to support the revitalization of U.S. technology-based manufacturing. According to a recent congressional study specifically focused on the U.S. bioeconomy, Congress has introduced several pieces of legislation directly related to the bioeconomy over the past few years, including the Bioeconomy Research and Development Act of 2020, which was reintroduced in 2021; the Engineering Biology Research and Development Act of 2019; and the 2020 Securing Global Leadership in U.S. Science and Technology Act, which was also reintroduced in 2021. The Senate also passed the U.S. Innovation and Competition Act of 2021, which includes the Bioeconomy Research and Development Act of 2021. These pending bills, if signed into law, will provide a good basis for supporting the continued growth of the bioeconomy. Bioeconomy research will also follow the provisions of the recently signed Infrastructure Investment and Employment Act (also known as the Bipartisan Infrastructure Agreement), as well as the recently announced U.S.-led Net Zero World Initiative and the 2018 National Advanced Manufacturing Strategic Plan.

Taken together, these pending laws are a good start to supporting the national bioeconomy, but making the most of the potential of the bioeconomy will require a more substantial commitment from the U.S. government. Our subsequent report will discuss the federal government's recommendations for specific policy initiatives to further activate the U.S. bioeconomy — perhaps legislation similar to the Create Beneficial Incentives for Chip Production Act and the Promote American-Made Semiconductors (FABS) Act.

Why was it put on hold?

While the benefits of building a bioeconomy for the 21st century and beyond are clear and undeniable, the United States still has a great deal of work to do to address the barriers to science, technology, infrastructure, and commercialization and to translate potential into reality. Some of the work to address scientific and technological barriers is taking place in academic and private sector laboratories, and reaching their full potential will require basic research, development and infrastructure support that the federal government excels at. For example, the U.S. government has a history of funding the Industrial Revolution by linking digital design and simulation to manufacturing. The most famous examples are CAD/CAM for mechanical engineering and aircraft manufacturing and layout and simulation tools for designing semiconductor chips.

In this regard, the molecular biology revolution owes its credit to federally funded biomedical research, which has made great strides in synthetic biology (direct engineering of microbes and plants). However, for example, all data on genes, proteins and biosynthetic pathways used by microorganisms and plants need to be better generated, organized, cataloged and shared. Doing so will enable bioengineers to use a wide range of biotech digital design and production technologies that are logically equivalent to those used in industries that produce the iPhone, Tesla, and 787. This capability will enable bioproduction facilities to adapt to the variable responses of living systems, making them more difficult to scale than mass-produced cars or cell phones. There is no doubt that federal research support in this area will create additional platform technologies that will lead to unexpected advances, as it has done in DNA sequencing, DNA synthesis, and genome editing.

Infrastructure barriers may be a bigger obstacle to commercializing research progress. A major obstacle is the limited capacity of test benches and medium-sized facilities in the United States that innovators need to demonstrate that they can scale up the success of their labs and produce bioproducts that perform the necessary testing and validation steps adequately. Another obstacle in this area is that innovators seeking to mass-produce bio-based products must deal with the combination of a variety of specific facilities and processes that are likely to be built without their products in mind. Investments in a network of new test bench facilities, as well as data and technology transfer standards similar to the application programming interfaces used in the software industry, will allow data to be applied directly from the lab to high-performance bioproduction, helping new products to market faster. It therefore makes sense to develop a biotechnology operating system that facilitates experimentation, optimizes production processes, facilitates the implementation of technology transfer, and integrates basic product development with the management of customer-facing production and compliance. Given the variability of biomass composition, biofabrications need to standardize on a variety of tasks from data collection and annotation to root-cause analysis, which facilitates the use of modern process development and management tools, just as there are far fewer variations in the chemical industry to handle their raw materials.

In addition to this, the transition from an oil-based one-time economy to a circular bioeconomy also involves one-time costs, estimated to cost about $145 billion over the next 30 years, which is slightly higher than the 25 percent of new federal spending under the Bipartisan Infrastructure Act — but these spending have a limited duration and will be rewarded multiple times once the transition is completed. As the saying goes, we need to stop doing things in the old, unsustainable way — and if we continue, the conversion of carbon sequestered in the form of oil, gas, and coal into carbon dioxide and other products can cause environmental damage and endanger life on Earth — and we have the ability to do it better.

Another constraint to the development of bioproductive capacity here is the severe shortage of bioprocess engineering talent in the United States, which increases the need for bioprocess engineering education at all levels, from community colleges to graduate schools. While our subsequent reports will explore labor demand more fully, it is only important to note here that other countries are actively addressing the issue. For example, the European Union has long developed high-quality research and training programs for chemical engineering and process development, while U.S. companies are increasingly forced to rely on foreign-trained talent. Today we often hear companies say they have to rely on process engineers in the Netherlands, for example, trying to recruit people to operate the facility for them.

Finally, countries need to be modernized to support the regulatory and policy needs of the bioeconomy. Our subsequent reports will discuss ways to address these issues, and will also identify a range of significant challenges and actions that are relevant to the bioeconomy and will benefit a range of communities, and develop implementation plans.

We need to do something

Can America's circular bioeconomy be realized?

The research, development and infrastructure opportunities highlighted in this report and recommended for public and private action fall into two broad categories: basic science and technology challenges and "end-to-end" biocapacity capacity (see Figure 1). Addressing the major scientific and technological challenges in creating a circular bioeconomy and achieving a net-zero economy will enable the country to unleash knowledge wealth, entrepreneurial dynamism and venture capital resources that are rarely available in other countries. Increasing "end-to-end" bioproduction capabilities will enable the nation to restart the "innovate here, produce here" model, develop the U.S. bioeconomy, and create millions of high-paying bioproduction jobs.

Figure 1: The relationship between developing basic scientific and technological capabilities, developing bioproductive capacity and the net zero goal The green arrow indicates the path to net zero dependent on biological production, and reflects the theme of this reportThe blue arrow indicates other paths to achieve net zero that are not dependent on biological production Image source: This figure was established with the assistance of Dr. Sifang Chen, a postdoctoral researcher at the Engineering Biology Research Consortium

U.S. government investments in these areas will be used to address challenges and remove barriers that will unleash the power and capacity of the private sector to create markets and drive economic prosperity, and address the nation's urgent need to transition to a sustainable, net-zero carbon economy that benefits all Americans. In addition, federal investment in basic science and technology has long been creating unexpected future applications, including research that has created a revolution in molecular biology as a cornerstone of the bioeconomy.

At the same time, industry plays a key role in these efforts, particularly in sharing knowledge and expertise through research partnerships with governments and academia. For example, partnerships between large technology companies and bioproduction companies with AI expertise, understanding the challenges of scaling up and being able to generate large amounts of data in the process can greatly reduce the time it takes to reach commercial production capacity. In fact, much of the entrepreneurial and investment activity in the bioeconomy is focused on the convergence of automation, software, and biology.

Of course, other organizations have developed roadmaps that can broadly support basic science and technology research, and these roadmaps will help promote the development of a vibrant bioeconomy. In particular, the Engineering Biology Research Consortium has developed several roadmaps for specific areas of basic research related to bioeconomy, including its latest roadmaps for engineering biology and materials science. This work differs in that it focuses specifically on research and development activities to expand "end-to-end" bioproductive capacity to reach the scale needed to move the U.S. bioeconomy into a circular bioeconomic economy and accelerate the transition to a net-zero economy.

Basic scientific and technological challenges

To achieve the maximum return on state investment, past and future, the U.S. government needs to accelerate its research into basic bioengineering and bioproduction. So far, U.S. federal support for research has helped researchers develop ever-improving tools, such as CRISPR, to freely manipulate DNA, and to use these tools to develop plant, microbial, and cell-free systems that can be used to mass-produce commercially valuable chemicals and materials. In order to increase a country's bioproductive capacity, R&D efforts need to focus on creating sound designs for bioproduction processes, including the following:

• Model, design and test metabolic pathways to create molecules and products that do not exist in nature;
• Developing rules, developing data analysis tools, improving computer modeling capabilities, and data-driven modeling protocols that enable biotechnologists to quickly identify and produce precise genetic modifications in the most appropriate organisms or cell-free systems to create, design, and test metabolic pathways and manufacture the biochemical products needed;
• Use emerging machine learning and artificial intelligence for data-driven discovery. Chemical engineers, materials scientists and some early adopters of industrial biotechnology are currently using these technologies;
• Accurate application of laboratory-scale results to industrial-scale production processes;
• Do everything in days or weeks, not months or years.

At the same time, research is being carried out to expand existing DNA production methods in order to create complete genes and even genomes with high precision. This requires the development of genetic tools for simultaneous and precise editing of plant and microbial genomes at multiple points to improve existing metabolic pathways and incorporate rational designs to create new metabolic pathways. Given the important role biomass has for the future bioeconomy, we need to pay more attention to the study of plant genomics and the extensive manipulation of plant genomes. For example, with funding from the National Science Foundation (NSF), scientists have successfully collected, annotated, and compared 26 different maize genomes to improve the productivity of food and feed crops and to develop varieties that can be grown on marginal land. Another research goal is to identify organisms, or even collections of organisms that work together, as new "chassis" for biological production to expand the range of products that can be routinely produced.

Creating biological systems capable of producing valuable chemicals and materials is just the beginning. Next, process and chemical engineers must develop the systems and technological capabilities needed to enable the production of large-scale commercial biological products. A related example is the transformation of a family-run beer fermenter into a full-fledged brewery that enables it to produce enough beer to supply every liquor store, bar and restaurant. While many companies have been able to achieve large-scale commercial production of existing products, some domestic start-ups are working hard to develop and acquire such capabilities. They do this for a number of reasons, as detailed in the section below on improving "end-to-end" bioproductive capacity.

For a number of reasons, it is not easy to expand the scale of biological production from small workshops to commercial production scale, such as the manipulation of living organisms is naturally variable. Therefore, we need to develop ways to deal with this variability and improve the efficiency of extracting related substances from biological feedstocks. In addition, governments can create markets for the individual carbon components (from one carbon to six carbons) produced by biological production, as well as the lignin of aromatic compounds, creating a carbon building block pipeline for the bioeconomy, as these carbon components can be embedded in existing value chains and infrastructure (Figure 2). Studies of tolerance to mixtures of impurities and biomass will also enable this shift in production scale.

Figure 2: A hypothetical carbon building block pipeline using biomass will produce carbon feedstocks for a variety of consumer and industrial products | Luis Cascão-Pereira

This requires more powerful modeling and simulation capabilities. To facilitate the development of these capabilities, we need funding to build a more accessible national computing and database infrastructure that supports the design-build-test-learn process common in bioengineering through better simulations. This infrastructure will provide process engineers with the ability to scale up experiments and improve operating conditions, then apply lab-based processes to small-scale trials and finally to large-scale commercial production. At present, such scale-up experiments are expensive and time-consuming, so we need to conduct collaborative research to optimize and standardize bioproduction scaling up.

This is an area that has not received much attention, but is critical for achieving a future circular bioeconomy, with a core mission that studies how to deal with the wide range of raw materials available to biotechnologists, including multiple types of forest-based biomass, grasses and crops, by-products of agriculture and aquaculture, by-products and waste from food production, municipal waste, wastewater and carbon dioxide produced by other processes, as well as other factors that depend on the geographical location of the bioproduction facility and the production season.

Due to the variability of biomass feedstocks, it is not possible to determine the optimal process conditions in advance. Bioproduction facilities can draw on the oil industry. The oil industry uses advanced computer modeling to adjust process conditions and fully convert each batch of crude oil into pre-determined chemicals. By using the same type of analytical tools and modeling, bioproduction facilities will be able to adapt their processes to the variability of biomass feedstocks caused by seasonal and geographical changes.

Once the United States achieves raw material flexibility or further improves its ability to use renewable biomass from different sources to promote the development of the bioeconomy, it is possible to turn one of the most headache-inducing wastes, plastics, into treasure. Researchers are investigating how existing plastics can be broken down into smaller molecules and used as feedstocks for biological production.

One advantage of this approach is that there is a ready-made plastic collection and sorting system. However, breaking down plastics into usable feedstocks is a relatively new and developing technology that needs to be studied on how to better combine plastics with biomass feedstocks. That said, the world's major polymer producers are investing in chemical recycling infrastructure, and some of these process technology developments are expected to bear fruit within the next 15 years. The U.S. should now make a larger strategic investment to take full advantage of this alternative raw material.

The U.S. has a vast pool of professionals in biotechnology and artificial intelligence, which allows the U.S. to meet these research needs with appropriate government support. However, our research on U.S. government support to develop its vibrant circular bioeconomy shows that U.S. government funding has not increased for years (Figure 3). If the U.S. really focuses on rebuilding its manufacturing capacity, creating millions of high-paying jobs across the country, and achieving a "net zero economy," the U.S. government should invest more immediately. The money needed to achieve this goal may be a fraction of the cost of the recently adopted bipartisan infrastructure agreement, and the return on this investment will be enough to justify it.

Figure 3: Federal Agency's Approach to Federal Research Grants in Bioeconomy-Related Fields (2006-2021): The visualization above was produced with the assistance of USASpending.gov, an official public data source website on federal spending. The type of incentive chosen was government subsidies, which excluded services such as consulting, military contracts, and modernization of IT infrastructure. The terminology used in the study was "biomass, bioprocessing, biofuels, raw materials, bioeconomy, bionutrients, bioprocessing, biofabrication, synthetic biology, cell-free synthesis, cell agriculture, downstream processing, scale-up production, biotechnology, and solid-state fermentation." The selected awarding agencies are the Department of Agriculture (USDA), the Department of Commerce (DOC), the Department of the Interior (DOI), the Department of Defense (DOD), the Department of Energy (DOE), the National Aeronautics and Space Administration (NASA), the Department of Health and Human Services (HHS), the International Development Agency (USAID), the Department of Homeland Security (DHS), the Environmental Protection Agency (EPA), the National Science Foundation (NSF), the Department of Veterans Affairs (VA), and the Smithsonian Institution | Kathryn Hamilton and John Haley, Aurora, North America

"End-to-end" bioavailability

While the scientific and technological and engineering communities are poised to address these basic science and technology challenges over the next five years by providing appropriate support, building nationwide end-to-end bioproductive capacity to scale up small workshop-style production to large-scale commercial production will require greater efforts and commitments from the U.S. government in this regard. This will be done in the next 3 to 15 years. This work will require progress in a number of areas, including research and development, infrastructure development, scientific and regulatory policy, and strategies for the development of alternative feedstocks. The risks that biotechnology products may pose in the future are an area of concern. The National Academy of Sciences, the National Academy of Engineering, and the Academy of Medicine have studied the topic in detail and concluded that there are no new or unique risk endpoints for current or future bioeconomy products that have not yet been addressed by the scientific community and regulators, but the complexity, scope, scale, and pace of progress of bioeconomical products may test the capabilities and expertise of regulators.

Development, pilot platform, and deployment

In biotechnology, products and processes are highly integrated. Technological innovation in European universities is ahead of the United States, while process innovation in the United States is basically non-existent. In the United States, manufacturing is considered an outdated industry, and students or teachers are not at all interested in manufacturing. It's hard to hire real process engineering talent in the U.S., and bioengineers who have just graduated from college are more likely to work in microbiology or synthetic biology without proper training in scaling up technology or designing processes.

Incentivize industry and academia to pursue innovation that will increase the capabilities of bioproduction technologies by a factor of 10 to the scale needed to achieve commercially viable alternatives based on an oil-based economy. Funding should be used to help scientists address major challenges in bioproduction over the next 5 years, just as the semiconductor and nanotechnology industry did in the past through state-funded programs. In general, the improvements required in bioproduction are not just about taking advantage of fermentation processes, but in this regard, chemical engineers can play an important role in applying the chemical production skills they have developed to a new industry with huge growth prospects and social benefits.

In addition to investing in solving the huge challenges in bioprocessing and bioproduction, there is a need to create a nanolithography industry using the model used by the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs. Increase the SBIR/STTR Fund dedicated to bioprocessing and bioproduction improvements by 10 times to foster innovation, develop mechanisms to streamline the SBIR/STTR funding model and revise regulations related to commercialization funding, which would otherwise hinder the commercialization prospects and business development of small businesses in the long run.

There is also a need to support so-called testbed facilities or sandboxes in this area, to scale up equipment that can be specialized in production, and to quickly transfer knowledge related to scale-up to innovators. The Bioinduct manufacturing and design ecosystem (BioMADE) is one example.

The Institute's key practice areas are to promote investment in related infrastructure and reduce investment risks. A seven-year incentive program supports this, including at least $87.5 million in federal funding from the Department of Defense and $180 million from other sources.

This facility, and similar facilities, will serve the bioproduction industry in the same way that ARPANET serves the development of the Internet. Other examples include the National Cancer Institute's Nanotechnology Characterization Laboratory, which will provide the analytical expertise needed to commercialize nanotechnology-based products, but these technologies are too expensive and difficult to access for small companies. Also included is the National Center for Wind Energy Technology at the National Renewable Energy Laboratory, which provides field validation sites and pilot facilities for composite manufacturing that have played a key catalytic role in the advancement of wind energy technology, benefiting the entire industry. Such a network of industry-enabled facilities would provide the ability to evaluate multiple bioengineering technologies in a "rapid failure" approach.

Infrastructure development

An important obstacle to translating laboratory research into commercial production is the lack of test bench facilities. Through the testbed facility, innovators can work with process and chemical engineering experts to develop scale-up and innovative manufacturing technologies that enable them to bring products to market faster at a lower cost. The National Institute of Standards and Technology (NIST) established the National Institute for Biopharmaceutical Manufacturing Innovation (NIIMBL) in 2016 as a public-private partnership to address the challenges of the biopharmaceutical industry. Just as NIIMBL invests in biopharmaceutical production, investing in bioprocessing basic science in pre-competitive areas will benefit the industry as a whole. It both helps industry practitioners gain knowledge and provides an opportunity for innovators to demonstrate that their processes can be commercialized on a medium scale before capital markets are involved in the construction of large-scale commercial facilities. The U.S. federal government can be a catalyst by establishing a network of regional test bench facilities that can use multiple organisms to process a variety of raw materials and produce multiple products at multiple scales, enabling innovators to develop scaling processes and generate performance data that lay the groundwork for a move to commercial production. Market risk makes the capital market still in a wait-and-see state, and the above practice will reduce market risk.

There are already domestic contracts for bioproduction facilities, but many of them have begun to serve the biopharmaceutical industry and operate under GMP standards. Because of the high fees of these for-profit contract facilities, bioeconomy startups struggle to compete with biopharmaceutical companies when trying to develop products that cost less than biomedical products or even cosmetic ingredients per pound. The U.S. government has paid a large deposit to address certain limitations on biological production capacity. BioMADE is the latest example of a PPP testbed bioproduction facility that, once completed, will aim to address certain needs in the bioeconomy sector. Another such facility is the Advanced Biofuels and Bioproduct Process Development Unit (ABPDU), which received funding in 2009 as a reflection of infrastructure investment under the U.S. Recovery and Reinvestment Act. The demand for this Department of Energy-administered facility at lawrence Berkeley National Laboratory is so great that it can't meet the needs of potential customers. Despite investment from the federal government, many companies have had to look for contract manufacturers in Belgium, Canada, China, Germany, India, Mexico, the Netherlands, Slovakia, Slovenia and elsewhere to obtain the necessary infrastructure that cannot be provided domestically. In addition, there is no comprehensive publicly available documentation of the location and function of existing domestic bioproduction facilities, unlike in Europe.

As a result, the Working Group initially compiled an information on existing bioproduction facilities and infrastructure to show the geographical location of a facility and whether the facility was publicly or privately owned. This information can be used as a basis for the future construction of a public database (Figure 4).

Figure 4: Public and private bioproduction facilities green, blue green and navy blue represent private, university-affiliated or public biomanufacturing plant solid circles and hollow circles represent whether the plant is active and unknown |, respectively This diagram was created with the help of Dr. Albert Hinman, a postdoctoral researcher at the Engineering Biology Research Consortium

In terms of international competitiveness, if the U.S. goal is to achieve international leadership, the U.S. must now act to build more such facilities, as other countries are already doing so. For example, the UK has established a National Centre for Biologics Manufacturing, a Process Innovation Centre and an Industrial Biotechnology Innovation Centre to promote the development of its emerging bioproducts industry. In the solar space, the U.S. federal government has failed to help fledgling companies through the mid-term development phase, which has played an important role in China's rise to become the world's leading supplier of photovoltaic cells. The same will happen to the U.S. bioeconomy if the U.S. does not act now and for the next five years to make strategic and aggressive investments in bioproduction infrastructure.

In addition to funding testbed facilities, the U.S. government could expand biological production capacity by encouraging the use of existing large-scale infrastructure. The U.S. government could also implement tax breaks, subsidies, loan guarantee programs, and other fiscal incentives to further invest in bioprocessing infrastructure and retrofit existing facilities, including existing idle cellulosic ethanol and pharmaceutical facilities, as well as corn-to-ethanol facilities for other bioproduction areas.

In addition, the U.S. government can support the emerging bioproduction hardware industry, perhaps by creating "plug and play" centers to provide a steady stream of bioproduction partners.

Such centers can focus their research on designing modular production systems that allow companies to scale up production relatively easily as demand for their products increases. Currently, because venture capital avoids funding independent equipment manufacturing companies, many startups in the bioeconomy sector have to design and develop hardware themselves, such as novel bioreactors, to increase their process yields.

recommend

The above discussion describes key U.S.-owned assets and key areas of research, development, and infrastructure that need to be further developed to take full advantage of those assets. As mentioned earlier in this report, regulatory and policy considerations are essential elements in support of the overall U.S. bioeconomy strategy. The working group will propose an overall strategy in March 2022, but here we will focus on the concrete actions needed to transform laboratory results into test bench production and eventually into large-scale commercial production to advance the current U.S. bioeconomic development and lay the necessary foundation for a future circular bioeconomy with net zero greenhouse gas emissions. We identified the following three requirements:

• Develop strategic bioproduction research plans to promote private and public sector innovation, thereby removing existing barriers to transformation;
• Establish and maintain creative public-private partnerships that disclose decades of hidden knowledge and data accumulated within the industry to accelerate technological transformation;
• Build and maintain a network of next-generation bioproduction test benches through infrastructure investments to stop the loss of offshore technology.

suggestion

1. The U.S. government should commit to maintaining its global leadership in bio-based sciences and to scale up production through the 5-year, $600 million Bioproduction Science Program (BSI), which expands the budgets and mandates of relevant scientific institutions to focus on how to advance current and future basic science and technology developments in bioproduction and remove barriers to the transformation of innovative technologies.

In a nutshell, innovations in bioproductive capacity can be achieved by improving the predictability of large-scale living systems and enabling modularization of bioproductives. Federal scientific agencies have made initial efforts on these big issues, but bolder efforts are needed to catalyze the necessary innovations. BSI should support the study of the significant issues detailed in this report and provide a high level of generalization here:

• Create metabolic pathway design software based on rules, data, and simulation capabilities for generating new molecules and products;
• Develop genetic and characterization tools for the study of microbial, plant and animal cells with biological production capacity or great potential, including tools for reading, multi-editing and writing whole genomes;
• Develop microfluidics and digital tools to enable predictive understanding of the likelihood of success from lab-scale to industrial-scale conversion through simulation, testing, data collection and iteration;
• Circularity is achieved through the development of next-generation bioproductive capacity, including modular production hardware, new software control systems, upstream enterprise flexibility for processing stocks of raw materials from local and other sources, and innovative downstream processing and programming activities for future investments in the biological field.

The National Science Foundation (NSF) should act as the lead agency for BSI to establish two regional innovation accelerators (RIAs) each year focused on bioproduction.

NSF supports basic research and education in all non-medical science and engineering fields, with a stated mission to "advance science, promote national health, prosperity, and welfare, and ensure national defense and security."

Given the project's inclusive terms of reference, the National Science Foundation is the ideal home for this multidisciplinary bioproduction science initiative. Through RIA and traditionally funded complementary research, NSF can implement these key research priorities, expand existing related funding, create new innovative industry partnerships, and advance the initial exploration of circular bioeconomy research.

RIA should establish new partnerships with relevant federal scientific agencies to build on existing expertise and leverage early-stage investments to achieve accelerated research coordination.

The FY2022 NSF budget request submitted to Congress describes riria as a vehicle for partnerships (industry, academic institutions, state and local government), but partnerships between federal agencies are not included in the description. Building partnerships between institutions with expertise can further accelerate the development of the bioeconomic economy and help break down silos between application areas.

For example, RIAs can work with the U.S. Department of Energy's ABPDU, Agile BioFoundry, and feedstock-Conversion Interface Consortium, and the U.S. Department of Agriculture's Feedstock Flexibility Program to advance basic research and expand future bioeconomy feedstock options.

2. The U.S. government should invest $1.2 billion over two years in a broad, flexible bioproduction infrastructure (bioproduction capable of processing multiple feedstocks with multiple microorganisms and producing multiple products on multiple scales) to expand domestic bioproductive capacity in a fair and strategic manner. More financial support is needed in the future to maintain and sustain these investments.

To maximize the potential of the U.S. bioeconomy and regain competitiveness, the U.S. needs to establish additional modular pilot-scale and medium-sized facilities with inherent flexibility, and it needs to be prioritized as an area of development.

The Ministry of Commerce shall, on the basis of the work of this working group, comprehensively evaluate the existing facilities and functions, so as to identify and seize opportunities to achieve an appropriate and fair layout of future facilities.

Operating such a facility requires improved access to raw materials, a trained workforce (or through training/retraining programs), and partnerships between academia and industry, as well as thinking about how this emerging industrial activity can maximize the benefit of the community.

A network of 10-15 new bioproduction facilities and refurbished bioproduction facilities, coupled with incentives for early technology development, will accelerate the transition from laboratory technology to commercial applications.

Previous federal bioproduction infrastructure investments, such as the Department of Energy ABPDU created under the U.S. Recovery and Reinvestment Act, NIST's NIIMBL, and the Department of Defense's Advanced Recycling Manufacturing Institute, have proven valuable in securing significant returns on federal investment, while the new Department of Defense BioMADE facility is also expected to deliver significant returns. However, these facilities are not enough to meet the growing demand of American innovators, who have to develop related technologies abroad.

In addition, the Department of Commerce should explore other financial incentives, such as those written into the CHIPS Act, to provide capital to small and large companies to meet their infrastructure needs.

Such incentives can take the form of tax incentives and loan guarantees, enabling companies to fund their new facilities and/or acquire and retrofit existing infrastructure as technology matures. This approach revitalizes communities with idle biological or chemical refineries.

3. To maintain global competitiveness, the U.S. government should establish and maintain creative public-private partnerships with the goal of "reducing the time required to successfully scale new products from years to months."

Given the lack of relevant academic research programs, much of the U.S. expertise in bioproduction exists in the companies involved and in the few publicly funded facilities currently in operation. As a result, the United States needs to take action to unleash decades of valuable hidden industry knowledge and data to accelerate technology transformation and unleash a wave of innovation.

The Department of Commerce should incentivize companies with deep AI expertise to partner with companies with biomanufacturing facilities to provide services, facilities and expertise to innovators.

New public-private partnerships can remove the barriers that innovators face to scaling up, such as the lack of bioproduction facilities, the lack of experience in technology transfer across scales, and the transfer of know-how and tacit knowledge. Participation in such partnerships may depend on spending a certain percentage of bioproductive time serving larger bioeconomical groups, making their products economically competitive from the start, or providing training or internship opportunities for the future bioeconomy workforce.

Conclusion

The convergence of platform technologies such as artificial intelligence and synthetic biology can accelerate the development of biotechnology solutions across multiple economic sectors, propelling the U.S. economy toward a resilient, sustainable, zero-carbon economic model. The huge underlying investment of the U.S. government has spawned the development of biotechnology. The United States can achieve a greater return on investment through its biotechnology-based economic model. In fact, as countries around the world embrace the circular bio economy, the United States should use its strong biotechnology expertise to take a leading position in the global circular bio economy based on biotechnology, which most countries cannot do. To do this, however, the U.S. government needs to make additional investments to facilitate the transition from a lab-scale to a commercial scale.

As noted in this report, the U.S. bioeconomy is poised to create huge economic and public benefits, but while new enabling technologies such as artificial intelligence and genome editing tools are rapidly evolving and will significantly accelerate the realization of a $4 trillion global bioeconomy, U.S. government investment in bioeconomy-related research has stalled over the past few years. However, to realize this vision over the next 5 years, the United States will need to make about $2 billion in new strategic investments in bioproduct R&D and infrastructure support.

The lack of bioproduction facilities and public databases, such as Europe's Pilots4U, has prevented U.S. industry from acquiring assets that help its technology mature. Several U.S. companies with emerging technologies have moved their operations overseas because of insufficient domestic productivity, giving other countries the technology rights that should have been acquired by the United States. The United States' immediate priority now is to bridge this gap, and the above proposals provide a road map to achieve this goal. In addition, the U.S. government still has the opportunity to create a proposed bioproduction scale facility and a new "business-to-business" information technology infrastructure that can be implemented, enabling innovators to develop innovative technologies while taking into account the compatibility of scale changes.

In short, through innovation in bioproductive capacity, biotechnology should be another set of tools for a zero-carbon future, providing workers and their communities with better bioproductive processes, cleaner and safer innovative technologies, and the means to combat and adapt to climate change. Now is the time for the United States to seize this once-in-a-lifetime opportunity to make the necessary investments to build a circular bioeconomy model of the future, based on the bioeconomy.

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