An improved bioproduction system for proteins and small molecules

全球对疫苗和治疗分子数量的需求正在增长。特别是植物，是多种生物活性小分子的来源，在植物中发现的许多天然产物被用作人类疗法。然而，这些化学物质通常丰度较低，或者在难以大规模培养的物种中产生，需要化学合成或将遗传途径转移到替代生物宿主以产生足够数量的化合物。虽然微生物已被证明在制造疗法方面非常强大，但有些不容易高产量生产。特别感兴趣的是能够对新的疾病威胁迅速作出反应的平台，例如疫苗的生产。植物已被证明能够有效表达治疗蛋白和次生代谢产物。在一个通常被称为“分子制药”的过程中，植物已被证明能够在短短几周内生产大量疫苗剂量。宿主的内源性代谢转移中间体或对表达分子进行不必要的修饰会使基因表达变得复杂。人们已经做了很多工作来定制特定的细菌和酵母菌株，以增加化合物的产量。然而，迄今为止，在改进工厂生产底盘上花费的努力很少，部分原因是缺乏可用的工具。现在的新技术使我们能够采取有针对性的方法来修改植物基因。我们已经确定了植物表达的可能对小分子异源生物生产有害的基因。我们现在将制作新的本烟（Nicotiana benthamiana）系列，这是一种来自北澳大利亚的烟草的近亲，它们在产生感兴趣的小分子方面的能力得到了改进。然后，我们将通过评估我们的新品系产生更多所需的新蛋白质和代谢物的能力，来衡量我们所做的改变的影响。这项工作将增加我们对植物代谢的认识，帮助我们了解它如何对扰动作出反应。它还将导致生产经过基因定制的植物，以生产不同类别的治疗分子

Global demand for quantities of vaccines and therapeutic molecules is growing. Plants, in particular, are the source of a great diversity of biologically active small molecules and a great many natural products found in plants are used as human therapies. However, these chemicals are often found in low abundance or are produced in species that are difficult to mass-cultivate requiring either chemical synthesis or the transfer of the genetic pathway to an alternative biological host in order to produce compounds at sufficient quantities. While microorganisms have proven to be exceptionally powerful for manufacturing therapies, some are not easily produced in high yields. There is particular interest in platforms that are able to respond rapidly to new disease threats, for example, the production of vaccines. Plants have been shown to be capable of efficient expression of therapeutic proteins and secondary metabolites. In a process commonly known as 'molecular pharming' plants have been demonstrated to be capable of producing a very large number of vaccine doses in just a few weeks. Gene expression can be complicated by the endogenous metabolism of the host diverting intermediates or performing unwanted modifications of expressed molecules. Much work has been done to tailor specific strains of bacteria and yeasts to increase production of compounds. However, to date, little effort has been spent on improving the plant production chassis, partly due to a lack of available tools. New technologies now allow us to take targeted approaches to modifying plant genes. We have identified genes expressed by the plant that are likely to be deleterious to heterologous bioproduction of small molecules. We will now make new lines of Nicotiana benthamiana, a relative of tobacco from Northern Australia, that are improved in their ability to produce small molecules of interest. We will then measure the impact of the changes that we have made by assessing the ability of our new lines to produce greater quantities of desirable new proteins and metabolites. This work will add to our knowledge of the metabolism of plants, helping us to understand how it responds to perturbation. It will also lead towards the production of plants that are genetically tailored for the production of different classes of therapeutic molecules