MRI: Development of a fully automated, 1,000-MicroChemostat microfluidic system for parallel, independent, long-duration, machine-guided experiments

MRI：开发全自动、1,000-MicroChemostat 微流体系统，用于并行、独立、长时间、机器引导实验

• 批准号: 2117782
• 负责人: John Wikswo
• 金额: $ 99.98万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2117782&HistoricalAwards=false
• 关键词: MRI; Development; fully; automated; 000

An award is made to Vanderbilt University to develop Genesis, a fully automated microfluidic system containing 1,000 microchemostats for parallel, independent, long-duration, machine-guided experiments to study microbial cells. Microbes such as the baker’s and brewer’s yeast Saccharomyces cerevisiae are expected to play an ever-increasing role in the production of vaccines, cancer therapies and other pharmaceuticals, food protein, and feedstock for the chemical industry, and sequestration of carbon dioxide from the atmosphere, all areas of pressing societal need. Genesis will use machine learning and artificial intelligence (AI) to serve as a “robot scientist” or “self-driving laboratory” to accelerate the development of mathematical models that describe microbial metabolism and growth. These will help us understand, and possibly optimize, for example, the interactions between the many different microbial species that comprise the human microbiome and contribute to both health and disease. The ability of Genesis to create computational models of cellular signaling and metabolism on its own should advance medicine, biotechnology, and fundamental biological knowledge, since such models are required to optimize experiments and interpret data to reveal the rules that govern biological processes. The Genesis project will involve three established research and training programs at Vanderbilt, all of which are active in the recruitment and involvement of undergraduate and graduate students and postdoctoral trainees in their research projects. Genesis offers a breadth of very attractive technical challenges and scientific and social opportunities ideal for interdisciplinary research training in AI, swarm robotics, machine learning, the exploration of signaling and metabolic pathways in microbes and suspended mammalian cells, and addressing how the complexity of biology could in fact be utilized to solve societal problems in nutrition, health, and medicine. Genesis will allow scientists and engineers and their trainees to address a number of important scientific, commercial, and societal problems by advancing our understanding of biology and disease and improving the efficiency of industrial production of biochemicals and pharmaceuticals. Genesis also provides additional impact as a tool for classroom instruction, in that ultimately it will allow students to pose questions and ask Genesis to design and conduct the experiments needed to answer them. Genesis will be designed to be mass produced at low cost, so that small laboratories could afford a small-scale system.In common use, yeast does its work in batches, where it grows and multiplies until it runs out of food or creates an environment where it can no longer thrive. A small batch of yeast grown in a research laboratory might require a milliliter of growth media in one well of a multi-well plate, whereas a yeast bioreactor at a pharmaceutical company could hold a few thousand liters, and one in a brewery a million liters. As an alternative to batches, a continuous-flow bioreactor, termed a chemostat, provides a steady supply of food and continuously removes excess yeast or even suspended mammalian cells and their metabolites to maintain steady-state growth. There is a growing recognition that chemostats can provide reproducible, reliable, and biologically homogeneous datasets that are well suited for probing the metabolism and signaling of living cells. However, the application of “self-driving” and machine-learning technologies to advancing biological knowledge will benefit from a thousand or more chemostats operating in parallel under computer control. Neither commercial production nor research chemostats have the correct combination of size, cost, and automated instrumentation. The Genesis system will address this need by using state-of-the-art, multi-channel microfluidic pumps and valves to control all of the microchemostats over a wide range of conditions with different strains of yeast, swarm robots to move 48 microchemostats at a time, and very high-throughput mass spectrometers to make a broad metabolic measurement every 10 or 15 seconds that will generate terabytes of data that exceed the ability of humans to control, process, and interpret. The resulting computational models could have thousands of equations. Genesis will provide, for the first time, an efficient means to design and conduct the massive number of biological experiments needed to parameterize, validate, and utilize these models to probe and even control biological systems for specific applications. Projects that will be pursued as soon as Genesis is operational include basic research in cell signaling and metabolism, quantitative explorations of the metabolomic interactions of co-cultured bacterial species that together could produce protein for food and chemical feedstocks, tracking multiple, parallel evolutionary histories to determine which environmental and genetic factors are important for the evolution of microbial cooperation, and improved methods to use mammalian cells to produce therapeutic antibodies. The parallel development of two Genesis instruments, one funded by NSF and the other by the Chalmers University of Technology in Gothenburg, Sweden, integrates Vanderbilt’s expertise in microfluidics and mass spectrometry with Chalmers’ expertise in AI, machine learning, and yeast to create a pair of robot scientists that will accelerate inquiries into the rules of life and the discovery of new solutions to some of society’s pressing problems.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.

授予范德比尔特大学开发Genesis的奖项，Genesis是一种全自动微流体系统，包含1，000个微型恒化器，用于平行，独立，长时间，机器引导的实验，以研究微生物细胞。微生物，如面包和啤酒酵母酿酒酵母，预计将在疫苗，癌症治疗和其他药物，食品蛋白质和化学工业原料的生产中发挥越来越大的作用，以及从大气中封存二氧化碳，所有这些领域都是迫切的社会需求。Genesis将利用机器学习和人工智能（AI）作为“机器人科学家”或“自动驾驶实验室”，加速开发描述微生物代谢和生长的数学模型。这些将帮助我们了解并可能优化，例如，组成人类微生物组并有助于健康和疾病的许多不同微生物物种之间的相互作用。Genesis能够自行创建细胞信号传导和代谢的计算模型，这将推动医学、生物技术和基础生物学知识的发展，因为这些模型需要优化实验和解释数据，以揭示控制生物过程的规则。“创世纪”项目将涉及范德比尔特的三个既定研究和培训项目，所有这些项目都积极招募和参与本科生、研究生和博士后学员参与其研究项目。创世纪提供了一系列非常有吸引力的技术挑战和科学和社会机会，非常适合人工智能，群体机器人，机器学习，微生物和悬浮哺乳动物细胞中信号传导和代谢途径的探索等跨学科研究培训，并解决了生物学的复杂性实际上如何用于解决营养，健康和医学方面的社会问题。创世纪将允许科学家和工程师及其学员通过推进我们对生物学和疾病的理解，提高生物化学品和药品工业生产的效率，解决一些重要的科学，商业和社会问题。创世纪还提供了额外的影响，作为课堂教学的工具，最终它将允许学生提出问题，并要求创世纪设计和进行所需的实验来回答他们。Genesis将被设计成以低成本大规模生产，这样小实验室就可以负担得起小规模的系统。在通常的使用中，酵母分批工作，在那里它生长和繁殖，直到它耗尽食物或创造一个环境，它不再能茁壮成长。在研究实验室中培养的一小批酵母可能需要在多孔板的一个孔中加入一毫升生长培养基，而制药公司的酵母生物反应器可以容纳几千升，啤酒厂的酵母生物反应器可以容纳一百万升。作为批次的替代方案，连续流生物反应器（称为恒化器）提供稳定的食物供应，并连续去除多余的酵母甚至悬浮的哺乳动物细胞及其代谢产物，以维持稳态生长。人们越来越认识到恒化器可以提供可重复的，可靠的和生物同质的数据集，非常适合探测活细胞的代谢和信号传导。然而，“自动驾驶”和机器学习技术在推进生物学知识方面的应用将受益于在计算机控制下并行运行的一千个或更多的恒化器。商业生产和研究恒化器都没有尺寸、成本和自动化仪器的正确组合。Genesis系统将通过使用最先进的多通道微流体泵和阀门来解决这一需求，以在各种条件下控制所有的微恒化器，不同的酵母菌株，群体机器人一次移动48个微恒化器，而且非常高-每10或15秒进行一次广泛的代谢测量，这将产生超过能力的TB级数据，控制、处理和解释的能力。由此产生的计算模型可能有数千个方程。创世纪将首次提供一种有效的手段来设计和进行大量的生物实验，这些实验需要参数化、验证和利用这些模型来探测甚至控制生物系统以用于特定的应用。一旦Genesis投入使用，将开展的项目包括细胞信号传导和代谢的基础研究，共培养细菌物种的代谢组学相互作用的定量探索，这些细菌物种可以一起为食品和化学原料生产蛋白质，跟踪多个平行的进化历史，以确定哪些环境和遗传因素对微生物合作的进化很重要，以及使用哺乳动物细胞生产治疗性抗体的改进方法。两台Genesis仪器的并行开发，一台由NSF资助，另一台由瑞典哥德堡的查尔默斯科技大学资助，将范德比尔特在微流体和质谱方面的专业知识与查尔默斯在人工智能、机器学习、和酵母创造了一对机器人科学家，这将加速对生命规则的探索，并发现一些社会紧迫问题的新解决方案。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。