Charting a Future for Sequencing RNA and Its Modifications A New Era for Biology and Medicine (2024) / Chapter Skim
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6 A Bold Vision for the Future of Sequencing RNA and Its Modifications: Conclusions, Recommendations, and a Path Forward
6 A Bold Vision for the Future of Sequencing RNA and Its Modifications: Conclusions, Recommendations, and a Path Forward
Pages 157-176
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For example, modified RNA molecules can, and are, being used to treat and prevent disease (Winkle et al., 2021) , grow synthetic biology applications (de la Torre and Chin, 2021)
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Conclusion 2: Sequencing the vast array of RNA molecules and discovering all modifications in all of their positions under various conditions and cellular states exceeds the challenge of the HGP. 158 Prepublication Copy
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Advancing Tools and Technology Determining the positions of all modifications on individual RNA molecules and elucidating their function in living systems will require significant technological advancement. Currently, there are tools Prepublication Copy 159
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• Indirect sequencing methods are high throughput and low cost, and importantly, provide positional information. However, they do not always provide information on the entire length of RNAs or enable discrimination of individual RNA molecules.
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and several other institutes and centers at NIH -- such as the National Institute of General Medical Sciences and the National Institute of Allergy and Infectious Diseases -- also fund research on RNA modifications.4 In terms of private foundations, The Warren Alpert Foundation has significantly invested in RNA modifications research and technology and infrastructure development to improve human health. 1 In 2022, NHGRI and NIEHS collaborated to host a virtual workshop "to determine the current capabilities, needs, and prospects for comprehensive characterization and understanding of the true diversity of all RNAs and their modifications at a chemical and structural level in relation to normal and disease states." See https://www.niehs.nih.gov/news/events/pastmtg/2022/rnaworkshop2022/index.cfm (accessed November 15, 2023)
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Roadmap for Advancing Tools and Technologies Within 5 years: • Standardize sample isolation, preparation, and handling methods for global analyses. • Establish RNA core centers that offer a range of expertise, techniques, and methods spanning the sequencing approaches (e.g., global modification mapping, direct and indirect sequencing)
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• Profile RNA modifications in human diseases. Prepublication Copy 163
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On standards, the committee agrees that: • A broad collection of modified RNA reference materials is needed to support efforts in fundamental research and tool and technology development. Such reference materials need to be technology agnostic and include modified nucleosides and oligonucleotides of known sequence and modification stoichiometry.
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With the establishment of data and database standards, it could also be possible to have seamless access to universally available and shareable information on RNAs of any biotype from any defined set of cellular conditions, including their modification status and their biological, medical, and functional properties. The committee developed milestones and deliverable to achieving this vision (Figure 6-3)
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● Database standards: o Put in place a financial mechanism for ensuring the long-term sustainability of critical RNA databases. o Promote a sustainably funded, stable, integrated, and centrally managed data resource that is a long-lasting and always-current source of curated information about modified RNAs.
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Chapter 5 describes the current needs for the education and training of a workforce specific to the RNA modifications field. On education, training, and workforce development, the committee agrees that: • The study of RNA and its modifications is an increasingly interdisciplinary endeavor, and training programs for the RNA modifications workforce need to reflect this.
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In particular, NSF can lead in this space because of their specific responsibility and mission for investing in research to expand knowledge in science, engineering, and education.9 Education and pedagogy experts, along with scientific societies with ties to the RNA research and broader life sciences communities, will also be important players in the education of future scientists who work in the field of RNA modifications. • Individuals already in the workforce can make important contributions to achieving the goals described above and to the application of epitranscriptomics.
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workforce with interdisciplinary expertise will be able to apply and advance sophisticated RNA biology, including epitranscriptomics, across the public and private sectors, academia, and industry. This roadmap is designed to aid in the development of education and training resources to build the future workforce for the RNA modifications field in the next 15 years (Figure 6-4)
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While the components listed above will help drive innovation, other factors are essential for transforming the field of RNA modifications. These other drivers include centralized facilities to perform specialized tasks, readily available, high-quality reagents and research materials, organization and coordination at the national and international levels, and a supportive policy environment (discussed in Chapter 5)
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For instance, the Warren Alpert Foundation, a sponsor of this study, recently funded research and technology development related to RNA modifications.10 The Margot and Thomas Pritzker Family Foundation has also committed funds toward establishing a plant biology center that includes research on how RNA modifications may impact plant growth and crop yields.11 Awards that support cooperative research efforts (e.g., multiple academic labs or academic–industry partnerships) will provide important opportunities for accelerated research progress.
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Dedicated funding to key federal entities -- such as NSF, NIH, NIST, DOD, and the DOE -- is critical to enhance their ability to work with academia, industry, philanthropic organizations, and international partners in driving innovation towards sequencing RNA and its modifications and ensuring translation of the resulting scientific breakthroughs into advancements including new, effective biotechnology products. 13 See https://arpa-h.gov/news/first-baa/ (accessed November 14, 2023)
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Investing time, effort, and money in developing the capabilities to determine any epitranscriptome will not only accelerate the understanding of the role that RNA modifications play in living systems and the molecular underpinnings for disease but will also facilitate the application of this knowledge to provide RNA-based solutions to issues in the fields of health and medicine, agriculture, synthetic biology, nanotechnology, environmental science, and beyond. If the information in this report is carefully considered and the recommendations implemented, the committee envisions a day when there will be higher crop yields, affordable treatments for many more human diseases, and vaccines for any infectious disease.
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