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Accelerating Biomanufacturing and Producing Cost-Effective Amino Acids through a Grand Challenge

05.15.23 | 14 min read | 文字Allison Berke

Summary

许多生物制造的产品需要氨基酸和生长因子作为投入，但是这些小分子和蛋白质可能非常昂贵，促进了生物制造的成本，从而减慢了美国生物经济的扩展，并限制了新型生物医学和合成的使用。农产品。制造成本可能是基本限制的：来自国立卫生研究院的官员，比尔＆梅琳达·盖茨基金会指向抗体药物作为主要瓶颈的制造成本在开发和分发各种现存和新兴传染病的治疗方法中。为了降低这些生物制造投入的成本，拜登 - 哈里斯管理局（Biden-Harris Administration）应分配联邦资金，以进行巨大的挑战，以研究和开发减少成本的制造过程，并证明这些解决方案的可扩展性。

氨基酸是重要的但昂贵的输入为洛杉矶rge-scale bioproduction. To reduce these costs, federal funding should be used to incentivize the development of scalable production methods resulting in production costs that are half of current costs. Specifically, the U.S. Department of Agriculture (USDA) and ARPA-H should jointly commit to an initial funding amount of $15 million for 10 research projects in the first year, with a total of $75. million over five years, in Grand Challenge funding for researchers or companies who can develop a scalable process for producing food-grade or pharmaceutical-grade amino acids or growth factors at a fraction of current costs. ARPA-H should also make funding available for test-bed facilities that researchers can use to demonstrate the scalability of their cost-saving production methods.

Scaling up the use of animal cell culture for biosynthetic production will only be economically effective if the costs of amino acids and growth factors are reduced. Reducing the cost of bioproduction of medical and pharmaceutical products like vaccines and antimicrobial peptides, or of animal tissue products like meat or cartilage, would improve the availability and affordability of these products, make innovation and new product development easier and more cost effective, and increase our ability to economically manufacture bioproducts in the United States, reducing our dependence on foreign supply chains.

为了更好地了解在生物制剂和基于动物细胞的产品的生产中使用氨基酸和生长因素，并准确预测供求，以确保医疗产品可靠且可用的供应链，国防部（国防部））和美国农业部应共同对普通生物产品的合成制造途径成本进行经济分析，并包括评估主要国际竞争对手的生产比较成本。

Challenge and Opportunity

Amino acids are necessary inputs when synthesizing protein and peptide products, including pharmaceutical and healthcare products (e.g., antibodies, insulin) and agricultural products (e.g., synthetic plant and animal proteins for food, collagen, gelatin, insecticidal proteins), but they are very expensive. Amino acids as inputs to cell culture cost approximately每公斤3至50美元和增长因素成本$50,000 per gram, meaning that他们的费用可能是一半或更高of the total production cost.

生物制造取决于再保险的可用性agents, small molecules, and bioproducts that are used as raw inputs to the manufacturing process. The production of synthetic bioproducts is limited by the cost and availability of certain reagents, including amino acids and small signaling proteins like hormones and growth factors. These production inputs are used in cell culture to increase yields and production efficiency in the biosynthesis of products such as monoclonal antibodies, synthetic meat, clotting factors, and interferon (proteins that inhibit tumor growth and support immune system function). While some bioproducts can be produced synthetically in plant cells or bacterial cells, some products benefit from动物细胞的生产步骤。一个例子是糖基化，这是一种蛋白质修饰过程，可帮助蛋白质折叠成稳定的结构，这在动物细胞中比细菌或无细胞系统中的过程要简单得多。疫苗发育中使用的病毒通常也在动物细胞中生长，尽管可以在酵母或昆虫细胞中生产一些重组疫苗。有benefits and drawbacksto the use of plant, fungi, bacteria, insect, or animal cells in recombinant bioproduction; animal cells are generally more versatile because they mimic human processes closely and require less engineering than non-animal cells. All cells, whether they are animal, plant or bacteria, require amino acids and various growth factors to survive and function efficiently. While in the future growth factors may no longer be required, amino acids will always be required. Amino acids are the most costly necessary additive on a price per kilogram basis; the most costly of the supporting additives are growth factors.

Growth factors are proteins or steroids that act as signaling molecules that regulate cells’ internal processes, while amino acids are building blocks of proteins that are necessary both for cell function and for producing new proteins within a cell. Cells require supplementation with both growth factors and amino acids because most cells are not capable of producing their own growth factors. Biosynthetic production in animal cells frequently uses growth factors (e.g., TGF, IGF) to increase yield and increase production speed, signaling cells to work faster and make more of a particular compound.

Pharmaceuticals

Although pharmaceutical products are expensive, relatively small demand volumes prevent market forces from exerting sufficient cost pressure to spur innovation in their production. The biosynthetic production of pharmaceuticals involves engineering cells to produce large quantities of a molecule, such as a protein or peptide, which can then be isolated, purified, and used in medicine. Peptide therapeutics is a$39 billion global marketthat includes peptides sold as end products and others used as inputs to the synthesis of other biological compounds. Protein and peptide product precursors, including amino acids and growth factors, represent a substantial cost of production, which is a barrier to low-cost, high-volume biomanufacturing.

For example, the production of antimicrobial peptides, used as therapeutics against antibiotic-resistant bacteria and viruses, is strongly constrained by the cost of chemical inputs. One input alone, guanidine, accounts formore than 25%of the approximately $41,000 per gram production cost of antimicrobial peptides. Reducing the cost of these inputs will have substantial downstream effects on the economics of production. Antimicrobial peptides are currentlyvery expensiveto produce, limiting their development as alternatives to antibiotics, despite a growing need for new antibiotics. TheU.S. National Action Plan for Combating Antibiotic-Resistant Bacteria(CARB) outlines a coordinated strategy to accelerate the development of new antibiotics and slow the spread of antibiotic resistance. Reducing the cost to produce antimicrobial peptides would support these goals.

这high costs of synthetic production limit the growth of the market for synthetic products. This creates a local equilibrium that is suboptimal for the development of the synthetic biology industry and creates barriers to market entry for synthetic products that could, at scale, address environmental and bioavailability concerns associated with natural sources. The federal government has already indicated an interest in supporting the development of a robust and innovative U.S.-based biomanufacturing center, with the passage of the CHIPS and Science Act and Executive Order 14081 on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy. Reducing the costs of basic inputs to the biomanufacturing process of a range of products addresses this desire to make U.S. biomanufacturing more sustainable. There are other examples of federal investment to reduce the cost of manufacturing inputs, from USDA support for新方法of producing fertilizer, to Food and Drug Administration investment toimprove pharmaceutical manufacturingand establish manufacturing R&D centers at universities, to USDA National Institute of Food and Agriculture (NIFA) support for thedevelopment of bioplastics和基于生物的建筑材料。联邦研发支持增加随后的私人研究资金and增加新产品的数量接收者发展，积极的创新度量。

降低生物制造成本的努力比任何一家公司都要大；因此，它需要在行业，学术界和政府之间进行协调的努力，以开发和实施最佳解决方案。成本效益生产前体的能力将直接和间接地推进生物制造的所有方面。学术界和工业准备好提高生物生产的效率和成本，但需要联邦政府的协调和支持，以实现这一基本里程碑，并支持大规模合成生物产品新兴行业的发展。

合成肉

开发具有成本效益的蛋白质和肽自己hesis would remove a substantial barrier to the expansion of synthetic medical and agricultural products, which would address current supply bottlenecks (e.g., blood proteins, antibody drugs) and mounting environmental and political challenges to natural sourcing (e.g., beef, soy protein). Over the past decade, breakthroughs in the manufacturing capability to synthetically produce biological products, like biofuels or the antimalarial drug artemisinin, have failed to reach cost-competitiveness with naturally sourced competitors, despite environmental and supply-chain-related benefits of a synthetic version. The Department of Energy (DoE) and others continue toinvestin biofuel and bioproduct development, and additional research innovation may soon bring these products to a cost-competitive threshold. For bioproducts that depend on amino acids and growth factors as inputs, that threshold may be very close.Proofof概念researchon growth factor and amino acid production, as well as techno-economic assessments ofsynthetic meat products, point to precursor amino acids and proteins as being substantial barriers to cost competitiveness of bioproduction—but close to being overcome through technological development. Potential innovators lack support to invest in the development of potentially globally beneficial technologies with uncertain returns.

Reducing the costs of these inputs for the peptide drug and pharmaceutical market could also bring down the costs of synthetic meat, thereby increasing a substantial additional market for low-cost amino acids and growth factors while alleviating the environmental burdens of a growing demand for meat. Israel has demonstrated that there is strong demand for such products and has大量投资于其合成肉类部门，这又增强了其整体生物经济。

Bringing the cost of synthetic meat from current估计of $250 per kg to the high end of wholesale meat prices at $10 per kg is infeasible without reducing the cost of growth factors and amino acids as production inputs but would also reduce the water and land usage of meat production by 70% to 95%. Synthetic meat would also alleviate many of the ethical and environmental objections to animal agriculture, reduce food waste, and increase the amount of plant products available for human consumption (currently77% of agricultural landis used for livestock, meat, and dairy production, and世界上有45％的农作物卡路里被牲畜食用）。

Bioeconomy initiatives and opportunity

Maintaining U.S. competitiveness and leadership in biomanufacturing and the bioeconomy is a priority for the Biden-Harris Administration, which has led to a national bioeconomy strategy that aims to coordinate federal investment in R&D for biomanufacturing, improve and expand domestic biomanufacturing capacity, and expand market opportunities for biobased products. Reducing the cost and expanding the supply of amino acids and growth factors supports these three objectives by making bioproducts derived from animal cells cheaper and more efficient to produce.

Several directives within President Biden’s National Biotechnology and Biomanufacturing Initiative could apply to the goal of producing cost-effective amino acids and growth factors, but a particular stipulation for the Department of Health and Human Services stands out. The 2022Executive Order 14081在推进生物技术和生物制造创新方面，以实现可持续，安全和安全的美国生物经济性，包括卫生与公共服务部（HHS）的指令（HHS）投资4000万美元，以“扩大活性药物成分生物制造的作用（APIS），抗生素，，以及生产基本药物并应对大流行所需的关键起始材料。”蛋白质和肽产品前体是医疗和药品产品的关键起始材料，证明HHS对这项研究挑战的支持是合理的。

国会还表明了其打算推进美国生物技术和生物制造。这筹码与科学法授权为可以扩大美国生物经济规模的项目提供资金。该法案的第四章，关于生物经济研究和发展的法案，授权研究研究床，用于扩展技术的测试床以及加速研究的工具。这种支持可以采用赠款，多机构协作资金以及小型企业创新研究（SBIR）或小型企业技术转移计划（SBTTP）资金的形式。

Biomanufacturing is important for national security and stability, yet much research and development are needed to realize that potential. The abovementioned funding opportunities should be leveraged to support foundational, cross-cutting capabilities to achieve affordable, accessible biomanufactured products, such as the production of essential precursor molecules.

Plan of Action

为了提供创新的催化剂，以降低零部件的价格，应向开发具有成本效益的生物合成生产途径的组织提供联邦资金。作为大挑战赛的一部分，最初的资金将在研究赠款的形式中最有帮助。大学的研究人员在开发具有成本效益的氨基酸合成方法方面取得了一些概念验证的进展，但是证明这些方法在大规模上取得成功所需的投资目前尚未由市场提供。合成生物制造输入（如氨基酸）的主要市场是药品产品，可以将高生产成本传递给消费者，并且不充分激励以降低投入的成本。

Recommendation 1. Provide Grand Challenge funding for reduced-cost scalable production methods for amino acids and growth factors.

这USDA (through the USDA-NIFA Agriculture and Food Research Initiative [AFRI] or through AgARDA if it is funded) and ARPA-H should jointly commit to $15 million for 10 projects in the first year, with a total of $75 million over five years, inGrand Challenge¹funding for researchers or companies who can develop a scalable process for producing food-grade or pharmaceutical-grade amino acids or growth factors at a fraction of current costs (e.g., $100,000 per kg for growth factors, and $1.50 per kg for amino acids), with escalating prizes for greater cost reductions. Applicants can also demonstrate the development of scalably produced bioengineered growth factors that demonstrate increased efficacy and efficiency. Grand Challenges offer funding to incentivize productive competition among researchers to achieve specific goals; they may also offer prizes for achieving interim steps toward a larger goal.

ARPA-H和美国农业部有条件刺激英诺华tion in cost-effective precursor production. Decreasing the costs of producing amino acids and growth factors would enable the transformative development of biologics and animal-cell-based products like synthetic meat, which aligns well with ARPA-H’s goal of supporting the development of breakthrough medical and biological products and technologies. ARPA-H aims to use its $6.5 billion in funding from the FY22 federal budget to invest in three-to-five-year projects that will support breakthrough technologies that are not yet economically compelling or sufficiently feasible for companies to invest internally in their development. An example technology cited by theARPA-H concept paperis “new manufacturing processes to create patient-specific T-cells to search and destroy malignant cells, decreasing costs from $100,000s to $1000s to make these therapies widely available.” Analogously, new manufacturing processes for animal cell culture inputs will make biosynthetic products more cost-effective and widely available, but the potential market is still speculative, making investment risky.

AgARDA was meant to complement AFRI, in its model for soliciting research proposals, and being able to jointly support projects like a Grand Challenge to scale up amino acids and growth factors provides reason to fund AgARDA at its authorized level. Because producing cell-based meat at cost parity to animal meat would be an agricultural achievement, lowering the cost of necessary inputs to cell-based meat production could fall under the scope of AgARDA.

Recommendation 2. Reward Grand Challenge winners who demonstrate scalability and provide BioPreferred program purchasing preference.

研究人员开发新颖的低成本和效率高iciency production methodology for amino acids and growth factors will also need access to facilities and manufacturing test beds to ensure that their solutions can scale up to industrial levels of production. To support this, ARPA-H should make funding available to Grand Challenge winners to demonstrate scaling their solutions to hundreds of kilograms per year. This is aligned with the test-bed development mandated by the CHIPS and Science Act. This funding should include $15 million to establish five test-bed facilities (a similar facility at the University of Delawarewas funded at $3 million）额外的300万美元，以提供10,000至300,000美元的凭证，用于测试床设施。（这些金额类似于vouchers由加利福尼亚能源部的清洁能源测试床计划提供。）

To support the establishment of a market for the novel production processes, USDA should add to its BioPreferred program a requirement that federal procurement give preference to winners of the Grand Challenge when purchasing amino acids or growth factors for the production of biologics and animal cell-derived products. The BioPreferred programrequires that federal purchases favor bio-based products(e.g., biodegradable cutlery rather than plastic cutlery) where the bio-based product meets the requirements for the purchaser’s use of that product. This type of purchasing commitment would be especially valuable for Grand Challenge winners who identify novel production methods—such as molecular “farming” in plants or cell-free protein synthesis—whose startup costs make it difficult to bootstrap incremental growth in production. Requiring that federal purchasing give preference to Grand Challenge winners ensures a certain volume of demand for new suppliers to establish themselves without increasing costs for purchasers.

利益相关者对这一巨大挑战的支持将包括研究大学；替代蛋白质，肽产物和合成蛋白质产业；支持降低肽药物价格的非营利组织（例如美国糖尿病协会或巨石肽基金会）和动物农业（例如新收获或好食品研究所）的降低；以及包括DOE和DOD在内的美国生物制造支持者。从事可伸缩氨基酸和生长因子生产的新方法的公司和研究人员还将支持技术 - 静态解决方案的额外资金（侧重于最终产品的特征而不是方法的解决方案，例如精确发酵，植物工程或细胞，- 无合成 - 用于获取产品）。

As another incentive, ARPA-H should solicit additional philanthropic and private funding for Grand Challenge winners, which could take the form of additional prize money or advance purchase commitment for a specified volume of amino acids or growth factors at a given threshold price, providing further incentive for bringing costs below the level specified by the Challenge.

Recommendation 3. To project future demand, DoD should commission an economic analysis of synthetic manufacturing pathway costs for common bioproducts, and include assessments of comparative costs in major international competitors (e.g., China, the European Union, the United Kingdom, Singapore, South Korea, Japan).

该分析可以部分通过BioMade的项目呼吁进行技术和创新研究来资助。BioMADE received $87 million in DoD funding in 2020 for a seven-year period, plus an additional $450 million announced in 2023. Cost sharing for this project could come from the NSF Directorate for Technology, Innovation, and Partnerships or from the DoE’s Office of Science’s Biological and Environmental Research Program, which has supported techno-economic analyses of similar technologies, such as biofuels.

EO 14081 also includes DoD as a major contributor to building the bioeconomy. The DoD’s Tri-Service Biotechnology for a Resilient Supply Chain program will invest $270 million over five years to speed the application of research to product manufacturing. Decreasing the costs of amino acids and growth factors as inputs to manufacturing biologics could be part of this new program, depending on the forthcoming details of its implementation. Advancing cost-effective biomanufacturing will transform defense capabilities needed to maintain U.S. competitiveness, secure critical supply chains, and enhance resiliency of our troops and defense needs, including medicines, alternative foods, fuels, commodity and specialty chemicals, sensors, materials, and more. China recently declared a focus on synthetic animal protein production in its January 2022 Five Year Plan for Agriculture. Our trade relationship with China, which includes many agricultural products, may shift if China is able to successfully produce these products synthetically.

Conclusion

为了支持美国境内广泛和敏捷的生物制造经济的发展，联邦机构应确保创建生物制造产品的必要投入尽可能丰富且具有成本效益。正如生产杏仁的成本在很大程度上取决于水的成本一样，在基于细胞的制造系统中生产生物产品的成本取决于用于喂养该系统的投入的成本。需要氨基酸和生长因子作为投入的生物制造产品范围从医学上必要的（例如凝血因子和单克隆抗体）到潜在的纪念性和行业改变，例如基于细胞的肉类和乳制品。联邦采取的行动提高在美国生产这些产品的可行性和成本效益将对生物经济和生物技术行业，制药和生物医学行业以及粮食和农业产业也有益地影响。