Science Policy

A “Focused Research Organization” to Systematically Study Bacteriophage Genes and their Functions

05.31.23 | 3分钟阅读 | 文本通过Sukrit西拉

Systematically sequencing the genome and studying the function of genes from all viruses that infect a set of model bacteria with significant scientific, biotechnological, and human health relevance will enable the development of phage-gene libraries that can in turn enable the faster development of genetic tools for advancing molecular biology.

Problem Statement

Viruses have been evolving host-modifying factors for billions of years. This wealth of naturally engineered proteins holds the key to unlocking the full potential of the cell. Virus-derived genetic tools have driven most key advances in molecular biology, from recombinant DNA to CRISPR genetic engineering. Although most such transformative discoveries have resulted from the study of bacteriophages (viruses of bacteria), phage research has relied primarily on inferential work rather than systematic approaches to discern the functions of phage genes. With serendipity as the primary engine of discovery, experimental approaches have not kept pace with phage genome sequencing over the past decade. Consequently, the vast majority of phage genetic diversity is still entirely unexplored.

Project Concept

We have built a high throughput screening platform to characterize phage genes and completed a pilot of the entire pipeline, from gene selection through functional screening and mechanistic follow-up (manuscript in preparation and available upon request). Our FRO will scale this platform and use it to chemically synthesize and test all non-redundant phage genes from two clinically relevant families of bacteria (Enterobacteria and Mycobacteria) which collectively host ~40% of all isolated phages, allowing us to test a large swathe of phage genetic diversity in a set of model species. The phage-gene library generated from this process will enable us to pursue the following objectives: 1) discover new molecular tools with revolutionary potential (eg. broadly understanding the principles of protein detection in antiviral immunity could yield a generalizable protein-targeting framework without some of the pitfalls of antibodies), 2) develop therapeutic avenues for antimicrobial resistant infections inspired by natural antiviral defense and counter-defense strategies, 3) build an inventory of phage design principles and engineering methods for therapeutic, industrial, and microbiome-directed applications, and 4) gain a complete understanding of interactions between phage and their hosts.

什么是专注的研究组织？

专注的研究组织（FROS）是时间限制的以任务为中心的研究团队，就像一家初创公司一样，以应对特定的中期科学或技术挑战。FRO项目旨在生产作为公共产品的变革性新工具，技术，流程或数据集，为研究社区创造新的功能，以更广泛地加速科学和技术进步。至关重要的是，由于激励措施，过程，任务或文化冲突，现有研究资金来源所留下的裂缝通常落在裂缝之间。代理商可以利用这些实体来实现其使命并提高科学进步的项目概念可能有很多项目概念。

This project is suited for a FRO-style approach because to achieve our scientific goals, we will need to scale our platform ~10,000-fold from 104-5 assays in the pilot to ~108-9 assays at the FRO. Massively parallelizing these assays will involve a highly systematic effort with a tightly coordinated and dedicated team, a substantial initial investment in gene-library synthesis and platform engineering, and long publishing timelines, which are qualities unsuitable for traditional grant funding. For these reasons, an FRO is the ideal (and probably the only viable) structure for this project.

How This Project Will Benefit Scientific Progress

Paradigm shifts in biology have often started with the humble bacteriophage. With 10^8-9prospects across the oldest and most diverse host-pathogen interface in the biosphere, our FRO presents abundant opportunities for making impactful discoveries, and will pioneer a new field of functional metaviromics. Moreover, the phage-gene libraries we will create are analogous to small-molecule screening libraries, consisting of 104-105 phage-derived natural products that can be used to find potentiators or suppressors of any cellular stressor of interest. We expect these resources to enable discovery far beyond the scope and timeline of our FRO.

Key Contacts

作者

• Sukrit Silas, University of California San Francisco,

Referrers

• 美国科学家联合会Matt Hourihan，mhourihan@www.tumejico.com
• Alice Wu, Federation of American Scientists,awu@www.tumejico.com

Learn more about FROs, and see our full library of FRO project proposals here.