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National Academies Report Amplifies Call to Develop Direct RNA Sequencing Technology


This story has been updated to include information on the National Academies study sponsors.

NEW YORK – The National Academies of Sciences, Engineering, and Medicine released a report on Thursday calling for a Human Genome Project-like effort focused on sequencing RNA and its epigenetic modifications.

The consensus study report outlines a 15-year plan for a public-private partnership to develop new methods that can directly sequence RNA molecules and detect the dozens, if not hundreds, of epigenetic modifications that can be found on them. Aside from technology development, key undertakings include developing RNA standards — likely with the help of the National Institute of Standards and Technology — cultivating an RNA-savvy scientific workforce, and creating new applications for the tools.

"To me, this really is the next step to the Human Genome Project," said Brenda Bass, an expert on RNA biochemistry at the University of Utah and co-chair of the National Academies committee that issued the report. One gene could make 100 different RNAs, she noted, and different RNA isoforms can carry different epigenetic modifications, of which more than 170 are known.

"I don't want to belittle the human genome, but there is so much information in RNA that isn't in DNA," Bass said. "If we want to understand a disease, we really need to know all the RNAs that come off of a gene and all the RNA modifications. This is going to change personalized medicine; knowing RNA modifications in plants could very well help us understand how to deal with food shortage especially with change in climate."

One big difference between this plan and the HGP is its end product. Whereas the latter was focused on producing a reference genome, a reference "epitranscriptome" doesn't really exist, Bass said. "What we need to do is push the technology so that at some point in the future, anyone will have the ability to sequence the epitranscriptome of their interest." The report mentions several extant technologies, including long-read sequencing and mass spectrometry, that partially address the needs of the field, but makes clear that new technologies are needed.

Another big difference could be in the price tag for the program. The committee was not tasked with estimating the costs of its proposals, Bass said, so it did not even attempt to do so. While the HGP came in at just over $3 billion in public funding, this project could be considerably less, according to Vivian Cheung, a researcher at the University of Michigan who has helped raise this call to action. Chueng reviewed the report but was not on the committee that wrote it. She suggested that $100 million a year might be enough to achieve the outlined goals. Moreover, she suggested that at that level it could be done in five years, not 15.

"I was hoping they'd be more aggressive" in their timeline, Cheung said. "[The report] lays out very clearly what the needs are, but 15 years is a long time given the urgency of what such a project can address, from biomedicine to food security. Hopefully we can get there much sooner."

The crux of the issue is that so-called RNA-seq technologies, with one major exception, do not actually sequence RNA. Rather, they sequence cDNA libraries prepared from RNA samples. That means almost all the epigenetic information is lost. And so far, most RNA-seq has been done with short-read sequencing, which cannot sequence many RNA isoforms with absolute certainty.

Of the existing technologies mentioned in the report, Oxford Nanopore Technologies long-read sequencing, which can detect some RNA modifications natively, checks the most boxes, but there are questions about its accuracy and ability to detect all the known RNA modifications. Mass spectrometry can detect many of the RNA modifications, but not at single-molecule resolution.

These limitations were outlined in a similar call for technology development made by researchers in the field led by Cheung and formally issued in a 2021 paper in Nature Genetics. Cheung proposed the topic to the National Academies, she said, and has continued to marshal people to the cause in parallel to the National Academies' efforts through an international consortium, the Human RNome Project, which also has the stated goal of sequencing RNA and its modifications.

With RNA modifications recently in the spotlight due to their crucial incorporation in the most effective COVID-19 vaccines, underscored by the 2023 Nobel Prize in Physiology or Medicine recognizing discoveries related to them, the RNA biology field is hoping to convince more people of their importance.

"Many people don't understand RNA modifications and why they're useful and why they're such a big deal," said Nicholas Adams, systems engineer in genetic sciences at Thermo Fisher Scientific and a member of the study committee.

The report highlights biomedicine, especially mRNA-based vaccines and gene therapies, but also includes instances where modified RNA could affect other industries, such as agriculture and biomanufacturing. For example, they noted a study that added a human gene for an enzyme that demethylates m6A, a commonly modified RNA base, to rice and potatoes, resulting in 50 percent increases in yields and biomass produced in both crops. These technologies will be ever more important as humans try to deal with the threat climate change poses to food security, the report said.

The Warren Alpert foundation sponsored the National Academies study with $1 million, joined by the National Human Genome Research Institute and National Institute for Environmental Health Sciences.

"There's a lot of effort and money going into proteome and genome, but there's just this gaping hole in the middle of it all," Adams said. "If you sit down and look at what's in front of you, this is the obvious place to sink in some dedicated effort."

The report's recommendations for technology developers and federal funding agencies address both the need for physical standard materials and standards for RNA data, especially to help determine the identify of modifications, and the need for technologies that can ultimately produce epitranscriptome data.

It presents a 15-year roadmap to achieving its recommendations, with three five-year intervals. For example, within five years it suggests standardizing sample preparation methods for RNA, establishing RNA core labs, and developing standards for RNA modification nomenclature. Within 10 years, it suggests completing the first "epitranscriptome map" of a simple, multicellular eukaryotic organism and the ability to synthesize long, modified oligos. Within 15 years, it calls for the ability to profile RNA modifications in human disease.

In their preface to the report, Bass and fellow co-chair, Taekjip Ha of Johns Hopkins University, noted that this effort will "need strong buy-in from the private sector." Adams noted that one of the lessons the committee learned from the HGP was that public-private partnership was essential to its success. "One thing we found interesting was that when the HGP kicked off, the technology didn't yet exist to accomplish their goals." High-throughput, automated capillary electrophoresis sequencers, such as the Applied Biosystems Prism 3700, were only introduced in 1998. "We found that optimism inspiring," Adams said.

The committee limited its speculation on what the final tools might look like, but did suggest that the ultimate solutions would see a combination of technologies working together, he noted.

"There's this faith in the trajectory of innovation," Adams said. "We cross our fingers that this will come. Based on our knowledge of history and patterns of tech development, you could put a lot of faith in that."