I-Corps: Unlocking constraints on mammalian cell programming using synthetic DNA and evolutionary selection

I-Corps：利用合成 DNA 和进化选择解锁哺乳动物细胞编程的限制

• 批准号: 2246452
• 负责人: Julie Trolle
• 金额: $ 5万
• 依托单位: New York University Medical Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2246452&HistoricalAwards=false
• 关键词: Corps; Unlocking; constraints; mammalian; cell

The broader impact/commercial potential of this I-Corps project is the development of genetically engineered mammalian cell lines that enable cells to grow in the presence of environmental stressors such as the lack of specific nutrients or in the presence of toxic waste products. Such cells may lower the costs of mammalian cell-based manufacturing, which is used in the synthesis of products that are critical to modern medicine such as biologics and cellular therapies as well as in the manufacturing of products that may reduce the carbon footprint of global agriculture such as cultivated meat. For example, cost parity of cultivated meat with conventional meat is not attainable with current technologies as over 95% of the cost of cultivated meat comes from the cost of adding recombinantly-produced growth factors to the culture medium to promote cell proliferation. Mammalian cells grown for cultured meat may be engineered to produce their own growth factors to reduce cost. Genetically engineering resilience in mammalian cells has the potential to bring the cost of performing large-scale mammalian cell culture down to a fraction of present-day cost.This I-Corps project is based on the development of a genetic engineering platform for mammalian cell programming. State-of-the-art technologies enable DNA writing into mammalian genomes at only the 10,000 base-pair scale. The proposed technology may allow genetic engineers to write 100,000 base-pairs into mammalian cells. This ability may allow the encoding of more complex sets of instructions that can specify sophisticated cellular behaviors and overcome the existing size constraints on biological programming. In addition, the proposed technology may be used to solve the knowledge constraint, i.e., selecting from an almost infinite number of equally (un)likely potential solutions to engineer a particular behavior. The platform is designed to rapidly prototype and test thousands of solutions in parallel. This work is based on technical results demonstrating the ability to enable mammalian cells to grow in the absence of valine, a canonically essential amino acid.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个i-Corps项目的更广泛的影响/商业潜力是开发基因工程哺乳动物细胞系，使细胞能够在环境应激源(如缺乏特定营养物质或有毒废物存在)下生长。这种细胞可能会降低哺乳动物细胞制造的成本，这种制造用于合成对现代医学至关重要的产品，如生物制剂和细胞疗法，以及用于制造可能减少全球农业碳足迹的产品，如栽培肉类。例如，目前的技术无法实现培养肉与传统肉类的成本平价，因为超过95%的培育肉成本来自向培养基中添加重组生产的生长因子以促进细胞增殖的成本。为培养肉类而培养的哺乳动物细胞可能会被改造为产生自己的生长因子，以降低成本。在哺乳动物细胞中进行基因工程的弹性有可能将大规模哺乳动物细胞培养的成本降低到目前成本的一小部分。这个i-Corps项目是基于哺乳动物细胞编程的基因工程平台的开发。最先进的技术使DNA只在10,000个碱基对的范围内写入哺乳动物基因组。这项拟议中的技术可能允许基因工程师将10万个碱基对写入哺乳动物细胞。这种能力可能允许对更复杂的指令集进行编码，这些指令集可以指定复杂的细胞行为，并克服现有的生物编程的大小限制。此外，所提出的技术可用于解决知识约束，即从几乎无限数量的相同(不可能)的潜在解决方案中选择来设计特定行为。该平台旨在快速制作原型并并行测试数千种解决方案。这项工作基于技术成果，证明了哺乳动物细胞能够在没有Valine的情况下生长，Valine是一种典型的必需氨基酸。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。