Algal oils by design: a new biotech platform for high-value lipids.

工业生物技术(IB)是利用生物过程和材料大规模生产工业有用的产品。IF为产品合成提供了新颖的解决方案，避免了化石燃料，而是使用植物、细菌、真菌和藻类作为可再生资源。这种生物经济目前在全球范围内价值数万亿美元，新的进展可能会给英国的工业部门带来重大好处，包括化学品、可再生能源、材料和健康，并可能在未来几年创造数千个就业机会。IB的一个主要领域是在工业规模的发酵罐中密集培养特定的微生物，在那里选择或设计微生物以生产高水平的所需商业产品，如抗生素、复杂的代谢物或治疗性蛋白质。这些发酵过程通常使用细菌或真菌作为“细胞工厂”。然而，一个非常庞大和多样化的微生物群体--藻类--是一种丰富的生物资源，尚未在生物技术行业中得到开发。这些光合作用微生物不仅提供了巨大的天然化合物宝库，这些化合物在药物发现中具有潜在的应用前景(例如，作为营养食品和食品添加剂，作为食品和化妆品中的天然着色剂或稳定剂)，而且还提供了利用阳光和二氧化碳来推动生物生产的可能性，而不是细菌或真菌生长所需的昂贵糖类。在这项提议中，我们的目标是开发藻类作为IB应用的细胞平台，并在这样做的过程中带来一种新的颠覆性技术。我们将以我们在藻类遗传学、生物化学和生理学知识方面的最新进展，以及基因工程和高通量细胞筛选技术的发展为基础。作为这个四年项目的重点，我们将开发藻类平台，最初用于生产高价值的油(=脂)，如可食用的omega-3和omega-6长链脂肪酸，这是动物饲料中的基本成分，并有助于婴儿大脑发育和成年人的认知功能。这个多学科项目有四个综合工作计划，并建立在五个参与小组的世界领先专业知识的基础上。我们将结合我们对选定的两个藻类物种的基因组、转录本和脂肪代谢组的生物学知识，以及先进的代谢建模工具，建立一个详细、稳健和可预测的藻细胞脂肪代谢模型。这样的模型将使我们能够在电子计算机中评估操纵脂质生物学的效果(例如，通过添加新的酶途径)。在第二个项目中，我们将利用我们在藻类基因工程方面的专业知识来开发合成生物学工具和设计管道，这将大大加快创造基因工程菌株的进程。这一点至关重要，因为即使使用复杂的模型，也需要评估大量不同的工程参数，以实现完全优化的应变。通过将基因工程与其中一个小组开发的高通量细胞评估技术相结合，也将促进这种菌株的选择。该系统包括将单个细胞封装在油微滴中，并使用与分析设备相耦合的微流控技术进行超快速分析和分选。这将使在大量群体中快速鉴定和恢复具有所需表型的稀有工程或突变细胞成为可能。最后，这些技术将被整合在一起，并在最终计划中进行测试，以确认我们可以设计和创造出能够生产高水平所需石油的“定制”菌株。

Industrial biotechnology (IB) is the harnessing of biological processes and materials for the production of industrially useful products on a large scale. If offers novel solutions to product synthesis that avoid fossil fuels, but instead use plants, bacteria, fungi and algae as renewable sources. This bio-economy is currently worth trillions globally and new advances could bring major benefits to UK industry sectors including chemicals, renewable energy, materials, and health, and could create thousands of jobs in the coming years. A major area of IB is the intensive cultivation of specific microorganisms in industrial scale fermentors, where the microbes have been selected or engineered to produce high levels of a desired commercial product such as an antibiotic, a complex metabolite or a therapeutic protein. These fermentation processes generally use either bacterial or fungal species as the 'cell factory'. However, a very large and diverse group of microorganisms - the algae - represent a rich biological resource that has yet to be exploited in the biotech industry. These photosynthetic microorganisms not only offer a huge treasure trove of natural compounds that have potential application in drug discovery (e.g. as nutraceuticals and food additives, as natural colorants or stabilizers in food and cosmetics) but also offer the possibility of cultivation using sunlight and CO2 to drive biological production, rather than the expensive sugars needed for bacterial or fungal growth.In this proposal we aim to develop algae as cell platforms for IB applications, and in doing so bring a new, disruptive technology to the fore. We will build on recent advances in our knowledge of the genetics, biochemistry and physiology of algae, together with developments in genetic engineering and high-throughput cell screening technologies. As a focus for this four year project we will develop the algal platform initially for the production of high value oils (=lipids) such as the edible omega-3 and omega-6 long-chain fatty acids that are an essential component of animal diets, and contribute, inter alia, to infant brain development and cognitive function in adults.The multidisciplinary project has four integrated programmes of work and builds on the world-leading expertise of the five participating groups. We will combine our biological knowledge on the genomes, transcriptomes and lipid metabolomes of two chosen algal species with advanced metabolic modeling tools to build a detailed, robust and predictive model of lipid metabolism in the algal cell. Such as model will allow us to evaluate in silico the effects of manipulating the lipid biology (for example by adding new enzyme pathways). In a second programme, we will use our expertise in algal genetic engineering to develop synthetic biology tools and a design pipeline that will greatly accelerate the process of creating genetic engineered strains. This is critical since, even with a sophisticated model, a large number of different engineering parameters need to be evaluated in order to achieve a fully optimized strain. Such strain selection will also be facilitated by integrating the genetic engineering with a high-throughput cell evaluation technology developed by one of the groups. This system involves encapsulation of single cells in oil microdroplets and ultra-fast analysis and sorting using microfluidic technology coupled to analytical equipment. This will enable the rapid identification and recovery within large populations, of rare engineered or mutated cells that have the desired phenotype. Finally, the technologies will be brought together and tested in the final programme to confirm that we can design and create 'bespoke' strains producing high levels of a desired oil.