Symbiosis and Chemical Diversity Generation

项目总结/摘要 我们的整体研究计划旨在了解化学多样性如何在生物体中产生， 将这种多样性应用于重要的生物医学问题。这个MIRA项目的重点是两个相关的科学 领域：1）以假设为基础的方法来发现新的生物合成途径和生物医学重要性 从海洋动物的化合物;和2）了解多样性产生的生物合成，并将其应用于 合成生物学该计划与我们的应用生物医学研究在药物发现和 发展，这是由其他地方资助。因为大自然是如何产生 我们的MIRA计划是提供创新的新材料和方法的关键， 生物医学应用的基础。我们解决两个首要问题： 1)海洋中的动物种类比其他任何地方都多，包括数百万种不同的动物。 物种许多海洋动物生活在高度竞争的环境中，因此它们或它们的共生体 细菌合成小分子化学防御，这已经被发现作为FDA批准的治疗方法的价值 和铅化合物。它们含有只有在海洋中才能找到的化学支架，而地球上其他任何地方都找不到。 虽然已经发现了许多重要的海洋动物天然产物，但生物和化学的 海洋的多样性几乎没有被触及。大多数海洋动物都太小、太稀有或太多变， 为药物发现和开发提供充足的化合物供应。在研究中， 通过这一计划，我们消除了发现新的潜在药物，酶， 动物的生化途径。我们采取假设驱动的方法来确定谁使海洋 天然产物（动物，共生体或其他）以及化合物是如何通过生物化学方法产生的。这项活动 直接导致发现和开发新的化学品和潜在的药物， 我们实验室的应用（非MIRA）侧。 2)动物物种含有化合物家族，而不是含有单一的生物活性天然产物， 其中个体动物具有母体结构的变体。有时，成千上万的变体来自一个 单一生化支架。在这种化学多样性的基础上，我们已经表明， 途径是多样性产生的，能够合成数百万种衍生物。这种不寻常的可塑性 被用作合成生物学的工具。在其他应用中，最令人兴奋的是能够 设计化合物，然后在不同种类的活细胞中生产它们。例如，基因库 我们已经创造了数百万种非自然的天然产物，我们正在开发基于细胞的 治疗在这里，使用假设检验，我们问如何多样性产生途径的功能：是什么使一个 途径塑料，以及如何在合理的合成生物学方法中使用这些功能。我们应用 在非MIRA的生物医学问题上的发现，我们实验室的应用生物医学方面。

Project Summary/Abstract Our overall research program aims to understand how chemical diversity arises in living organisms, and to apply that diversity to important biomedical problems. This MIRA project focuses on two related scientific areas: 1) a hypothesis-based approach to discovering new biosynthetic pathways and biomedically important compounds from marine animals; and 2) understanding diversity-generating biosynthesis and applying it to synthetic biology. The program synergizes with our applied biomedical research in drug discovery and development, which is funded elsewhere. Because so much remains to be learned about how nature produces diverse chemical scaffolds, our MIRA program is the key to providing innovative new materials and methods that underlie the biomedical applications. We address two overarching problems: 1) There is a greater variety of animal life in the sea than anywhere else, including millions of diverse animal species. Many marine animals live in highly competitive environments, and therefore they or their symbiotic bacteria synthesize small molecule chemical defenses, which have found value as FDA-approved therapeutics and lead compounds. They contain chemical scaffolds found only in the oceans and nowhere else on Earth. Although many important marine animal natural products have been discovered, the biological and chemical diversity of the oceans has barely been touched. Most marine animals are simply too small, rare, or variable to provide a sufficient supply of compounds for drug discovery and development. In research that will continue through this program, we eliminate the barriers to discovering new potential pharmaceuticals, enzymes, and biochemical pathways from animals. We take a hypothesis-driven approach to determine who makes marine natural products (animal, symbiont, or other) and how the compounds are made biochemically. This activity leads directly to the discovery and development of novel chemicals and potential pharmaceuticals in the applied (non-MIRA) side of our laboratory. 2) Instead of containing a single bioactive natural product, species of animals contain families of compounds, where individual animals harbor variants of a parent structure. Sometimes, thousands of variants arise from a single biochemical scaffold. Underlying this chemical diversity, we have shown that several biosynthetic pathways are diversity generating, capable of synthesizing millions of derivatives. This unusual plasticity has been applied as a tool for synthetic biology. Among other applications, one of the most exciting is the ability to design compounds and then produce them in different kinds of living cells. For example, genetic libraries encoding millions of unnatural natural products have already been created, and we are developing cell-based therapies. Here, using hypothesis testing, we ask how diversity-generating pathways function: what makes a pathway plastic, and how can these features be used in rational synthetic biology approaches. We apply the resulting discoveries to biomedical problems in the non-MIRA, applied biomedical side of our laboratory.