Symbiosis and Chemical Diversity Generation

项目摘要/摘要 我们的整体研究计划旨在了解生物体中化学多样性是如何产生的，并 将这种多样性应用于重要的生物医学问题。这个Mira项目关注的是两个相关的科学 领域：1)发现新的生物合成途径和生物医学上重要的基于假设的方法 来自海洋动物的化合物；以及2)了解产生多样性的生物合成并将其应用于 合成生物学。该计划与我们在药物发现和应用生物医学研究方面的协同作用 发展，这是由其他地方资助的。因为关于大自然是如何产生的，还有很多东西需要了解 多种化学支架，我们的Mira计划是提供创新材料和方法的关键 这是生物医学应用的基础。我们解决了两个主要问题： 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竞争激烈的环境中，因此它们或它们的共生 细菌合成小分子化学防御，已发现其作为FDA批准的治疗药物的价值 和先导化合物。它们含有只在海洋中发现的化学支架，在地球上其他地方找不到。 虽然已经发现了许多重要的海洋动物天然产物，但其生物和化学成分 海洋的多样性几乎没有受到影响。大多数海洋动物都太小、太稀有或太易变，以至于 为药物发现和开发提供充足的化合物供应。在将继续进行的研究中 通过这项计划，我们消除了发现新的潜在药物、酶和 来自动物的生化途径。我们采取一种假设驱动的方法来确定谁制造了海洋 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制成的。本练习 直接导致发现和开发新的化学品和潜在的药物在 我们实验室的应用(非MIRA)侧。 2)动物物种不是含有单一的生物活性天然产物，而是含有化合物家族， 其中个别动物拥有亲代结构的变体。有时，数以千计的变体产生于一个 单一的生化支架。在这种化学多样性的基础上，我们已经证明了几种生物合成 途径是产生多样性的，能够合成数百万个衍生物。这种不同寻常的可塑性具有 被用作合成生物学的工具。在其他应用程序中，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，基因文库 编码数以百万计的非天然天然产物已经被创造出来，我们正在开发基于细胞的 治疗。在这里，使用假设检验，我们询问多样性产生途径是如何发挥作用的：是什么使一个 途径塑料，以及如何将这些特征用于合理的合成生物学方法。我们将应用 由此发现的生物医学问题在我们实验室的非MIRA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.