Decoding RNA mysteries: a new era for biology and medicine

Published: August 1, 2024

RNA modifications critically influence the structure and function of RNA molecules, impacting health, biotechnology and agriculture. To overcome the challenges of sequencing RNA molecules and their modifications, we urgently need advances in sequencing methods and technologies. The US National Academies of Sciences, Engineering, and Medicine has assembled a committee of 16 professionals with a wide range of expertise related to RNA sequencing and RNA modifications, who call for a large-scale effort to revolutionise our understanding of RNA biology and unlock its potential. Part of the team is featured below.  

Talk like an RNA biologist

Epitranscriptome — the collection of all RNA modifications in a cell, which varies according to cell type and conditions

Gene expression — the process by which information from a gene is used to create functional products, such as RNA and proteins

Genome — the collection of all DNA in a cell, which is identical in every cell within an individual

Human Genome Project — an international scientific project that sequenced the DNA that comprises all of the genes in humans and uncovered the ‘human reference genome’

RNA modification — a chemical change to an RNA molecule occurring during or after transcription, which can influence the RNA’s structure and function

RNA sequencing — the process of determining the sequence of RNA molecules

Transcription — the process by which an RNA molecule is synthesised from DNA

Ribonucleic acid (RNA) is an essential molecule in all living cells. It undergoes various chemical changes that influence its function and stability, and these modifications can have profound implications for human health and disease, biotechnological innovations and even agricultural productivity. A recent report by a 16-member committee of the National Academies of Sciences, Engineering, and Medicine (NASEM), led by Professor Brenda Bass and Professor Taekjip (TJ) Ha, highlights the importance of sequencing RNA and its modifications, as well as the associated challenges.

What are RNA modifications?

RNA modifications are chemical changes to RNA molecules that happen during or after transcription. These modifications can alter the three-dimensional structure of RNA, change its abundance in a cell and influence its interactions with other biological molecules, all of which are important for maintaining life. “RNA modifications are known to be involved in regulating metabolism, circadian rhythm and the immune system,” says Brenda. “Research has also revealed that disrupting the cellular machinery responsible for editing and modifying RNA can lead to a wide range of diseases that include, but are not limited to, neurological disorders, heart disease, autoimmune diseases, cancer and diabetes.”

How can RNA modifications be beneficial?

“We’re still learning about RNA modifications, but what we do know has already been used to produce vaccines and medicines,” says TJ. “One prominent example is the development of mRNA vaccines during the COVID-19 pandemic, which used the N1-methylpseudouridine modification to make them safe and effective.” These vaccines saved millions of lives and showcased the potential of RNA technology to create new therapies. Additionally, RNA modifications can revolutionise personalised medicine by enabling a more precise understanding of gene expression in different individuals, opening new avenues for treating genetic disorders, cancers and other diseases.

“Beyond health and medicine, RNA modifications show exciting promise for enhancing agricultural productivity,” says Brenda. “For example, engineering of RNA modifications has demonstrated improved drought resistance and crop yields in rice and potatoes.” Such advancements have the potential to boost food security for billions of people across the globe by ensuring more resilient and productive crops in varying environmental conditions.

Why can we not determine a ‘human reference epitranscriptome’?

“As we began our work, we were inspired by the Human Genome Project and its impact on shaping our modern-day knowledge of the DNA sequence of each gene, and in some cases, gene variants that correlate with disease,” explains TJ. “But each gene gives rise to dozens, sometimes thousands, of RNA molecules. Importantly, these RNA molecules are also subject to biological processes that chemically alter, or modify, their sequences.”

Unlike the relatively stable DNA genome, in which the single ‘human reference genome’ can approximately describe all humans, the ‘epitranscriptome’ (the collection of all RNA modifications in a cell) varies significantly between different cell types and changes in response to developmental stages and environmental conditions. This dynamic nature makes determining a reference epitranscriptome infinitely more challenging than determining a reference genome, as each cell can have a unique and constantly changing set of RNA molecules. This makes it incredibly challenging to define a reference epitranscriptome for an individual, let alone an entire species. “We came to the consensus that our task should not be determining an epitranscriptome, but evaluating how to develop technologies and infrastructure that would enable the determination of any epitranscriptome of interest,” says Brenda. This approach would allow doctors to understand the epitranscriptome most relevant to their patient’s condition, and scientists to explore the epitranscriptome most relevant to their research.

What are the current limitations in RNA sequencing?

RNA sequencing faces several limitations that hinder our ability to fully understand RNA modifications. One major challenge is the lack of a single method capable of identifying and sequencing all known RNA modifications, of which there are over 170 different types. And in addition to chemical modifications, RNA is also more prone to degradation than DNA, meaning RNA can be degraded and lost during preparation before sequencing. Also, with current techniques, it is difficult to capture comprehensive modification data in a single experiment – there is not yet a way to identify every modification and its abundance. To advance the field, we need innovations that overcome these challenges and enable end-to-end sequencing of RNA molecules that preserves information about all its modifications, ideally in a single experiment.

Looking to the future

“What we know about RNA modifications is just the tip of the iceberg,” says Brenda. “If we can better understand RNA modifications by improving our ability to sequence and study them on any RNA molecule from any living system, the possibilities are endless.” This enhanced understanding could lead to significant advancements in our fundamental knowledge of living systems, which would greatly benefit human health, agriculture and the environment.

“All of the conclusions and recommendations of our report are important, but a key conclusion that ties much of this together is that there is a need for a large-scale scientific effort focused on epitranscriptomics,” says TJ. “The Human Genome Project is a great example of how focused and concerted organisation and funding directed towards a set of well-defined goals can accelerate technological innovation in a field.” By embracing a collaborative, well-coordinated approach, we can unlock the full potential of RNA modifications. This concerted effort will push the boundaries of science and inspire the next generation of researchers to explore the uncharted territories of RNA biology.

Professor Brenda Bass

Department of Biochemistry, University of Utah School of Medicine, USA

Professor Taekjip (TJ) Ha

Division of Medical Sciences, Harvard Medical School and Boston Children’s Hospital, USA

Fields of research: RNA biology, epitranscriptomics

Chairs of an expert report: Charting a future for sequencing RNA and its modifications: a new era for biology and medicine

Funders: The Warren Alpert Foundation, National Human Genome Research Institute, National Institute for Environmental Health Sciences

Pathway from school to RNA biology

RNA biology is the study of ribonucleic acid (RNA), an essential molecule in all living cells that plays a key role in processes such as gene expression and protein synthesis. “To pursue a career in RNA biology, exposure to a range of subjects such as chemistry, molecular and cell biology, and computer science (e.g., basic programming, data science) will be pivotal in ensuring that you develop the skills needed to emerge as a leader in the growing and increasingly interdisciplinary field,” explains Brenda.

Improving RNA sequencing and our understanding of RNA modifications requires interdisciplinary collaborations. We need people with expertise in molecular and cell biology, biochemistry, engineering, bioinformatics and policy to advance the field of RNA biology.

Developing both practical and transferable skills is essential for becoming an RNA biologist. These include laboratory techniques, computational competence for data analysis, and bioinformatics, along with soft skills such as critical thinking, problem-solving, communication and teamwork.

Explore careers in RNA biology

RNA biology is a highly interdisciplinary field that offers a broad range of career opportunities. “Biologists, chemists, biophysicists, bioengineers, computer scientists, technicians, bioethicists, communicators, and people working in science, medicine and technology policy all have a role to play,” says TJ. For example, biologists and chemists uncover the mechanisms and functions of RNA modifications, while bioengineers develop tools and technologies to manipulate and study RNA. Computer scientists and bioinformaticians analyse the vast amounts of data generated from RNA sequencing experiments, and technicians provide the hands-on support needed for laboratory research.

Careers in RNA biology can be found in academia, industry and government institutions. “You may find yourself working as a researcher at a university, like many of the committee members, or at a national research lab such as the US National Institutes of Health,” says Brenda. “You could also work as a scientist or engineer in industry.” In the biotechnology and pharmaceutical industries, scientists are taking advantage of RNA technology to develop innovative therapies and diagnostic tools. The recent success of mRNA vaccines during the COVID-19 pandemic highlights the profound impact RNA research can have on public health. Additionally, there are opportunities in science communication and policy, where professionals can influence public understanding and government regulations surrounding RNA technologies.

RNA biology is a very exciting field due to its profound societal impacts and diverse applications. “RNA modifications play roles in key molecular processes, are central to health and disease, and have a wide range of applications from medicine to agriculture to biotechnology,” says TJ. RNA biology is at the forefront of scientific innovation, with the potential to develop better vaccines, personalised medical treatments, and improved agricultural practices. By pursuing a career in RNA biology, you will have the opportunity to contribute to cutting-edge science that can make a significant difference in the world. It is these continuous advancements that promise a dynamic and impactful career, making it an exciting and rewarding field to pursue.

Reference
https://doi.org/10.33424/FUTURUM518

Lydia uses a pipette to prepare reagents for an RNA extraction experiment
Artwork by Dr Janet Iwasa showing modified ribosomal RNA as it translates the SARS-CoV-2 RNA genome
© National Academy of Sciences, all rights reserved
Sarath showcases a single molecule sequencer that can sequence RNA in real time – this device was widely used during the COVID-19 pandemic to sequence RNA in the SARS-CoV-2 virus
Nick tests a new genetic analysis technique in the lab
Lydia checks a bacteria culture growing in an incubator in her lab
Graduate students in Lydia’s chemical engineering lab (L-R): Alyssa Ekdahl, Sungyeon Jang, Lydia Contreras, Trevor Simmons, Lucas Miller, Katie Taylor and Agata Turula
Sarath and his colleague discuss computational approaches for studying RNA modifications

Meet some members of the team

Meet the full team: www.nationalacademies.org/our-work/toward-sequencing-and-mapping-of-rna-modifications#sectionCommittee



Professor Juan Alfonzo
Brown University

Fields of research: Microbiology, molecular biology

I wanted to be a scientist from an early age. I had read the works of Lavoisier and was familiar with the laws of physics, including Newtonian physics. My first love was chemistry but, during my undergraduate training at Indiana University Bloomington, I was inspired by the lectures of the late Professor Walter Konetzka, a microbiologist. I switched my major from chemistry to microbiology, which introduced me to molecular biology.

I am most proud of my dedication to teaching and training others, always speaking in a direct manner, while keeping it fun. I have no patience for egos! I’m lucky that I have correctly hypothesised the answers to many scientific puzzles I’ve worked on. With that said, for every correct guess, I failed miserably on a thousand others!

My contribution to the NASEM report started with a phone call from my friend Professor Vivian Cheung. It was her idea to put together a commentary on the current state of sequencing RNA and its modifications, and we then reached out to NASEM to increase the scope of the project.

I am not a sequencing expert, but I am very familiar with the advantages and disadvantages of current techniques to map RNA modifications. My contribution to the project is my deep knowledge of RNA modifications, which expands to organisms from all domains of life, not just a few modifications or single organisms.

We have learned a lot about RNA in recent years and yet, we still know very little. That alone should drive your curiosity! RNA biology offers plenty of fertile grounds for new discoveries.

Juan’s top tips

1. Work hard at answering your own questions.

2. Be curious and learn for the heck of it!


Professor Lydia Contreras
University of Texas at Austin

Field of research: Chemical engineering

I fell in love with science while I was at school. As a Latina immigrant, I was relieved to learn that math, chemistry and physics were a universal language. I could connect to others through science, which made me feel I belonged, even though I didn’t speak much English. Later, it was exciting to learn that these principles could be used to understand and make useful processes that could potentially benefit people.

As a chemical engineer, I innovate new methods to look at RNA in live cells, which involves designing appropriate biomolecular ‘tools’. I think of RNA as a dynamic system that has complex ways of sensing inputs and actuating outputs. My interest in thinking outside the box about processes and methods as tools for RNA studies contributed to the NASEM report, as we want to develop approaches to move the field of RNA modifications forward.

I am proud to inspire my students to think about science, and especially RNA, in new ways. As a professor, I am highly in-tune with the fact that curricular updates are needed to train and inspire the next generation of RNA scientists, which is another contribution I brought to the NASEM report.

Chemical engineering is a broad discipline, whereby knowledge of chemistry, physics, math, biology and other fundamental science is combined to understand and optimise chemical processes. In my case, these are biological processes but, in other cases, these can be processes that affect agriculture, drug design, oil and gas industries, food industries, materials science, etc.

Lydia’s top tips

1. I was the first scientist in my family. If you don’t know anyone in an area that interests you, dare to be the first one to pursue it!

2. Stay on top of your science classes and look for opportunities that reinforce the excitement you feel for science. In looking for opportunities, remember to ask questions about where these might exist – at times we forget that everyone asks questions.


Dr Kate Meyer
Duke University School of Medicine

Field of research: Biochemistry

Initially, I wanted to become a doctor, so I took pre-med courses in biology and chemistry when I started college. During a cognitive neuroscience course, I learned about rare but fascinating diseases that develop when certain parts of your brain don’t work correctly. I was drawn to the idea of figuring out the biology underlying these diseases and discovering cures. So I shifted my focus to research and gained experience working in different labs. Once I started doing hands-on research, I knew I had found my calling.

After completing my PhD in neuroscience, I joined a lab that studied RNA. At the time, I knew nothing about RNA modifications and felt out of my comfort zone for the first few months. However, I had an excellent mentor who supported me as I developed a technique to observe, for the first time, where a specific RNA modification existed. We realised it was in thousands of RNA molecules in our cells. I am proud of this study because it transformed the field and opened everyone’s eyes to how prevalent chemical modifications are in messenger RNA.

Now, I run a biochemistry lab studying RNA modifications. We use a variety of different techniques, including genetic manipulation of cultured cells, biochemical assessment of RNA-protein interactions, and studies with transgenic mice.

My expertise in RNA modifications and my knowledge of the various techniques used to study them were helpful for the NASEM report, especially the sections discussing the importance of RNA modifications, how they are regulated, and how they are studied. I also contributed to the discussions of what we, as a committee, think will be needed over the coming years to achieve the goal of determining any epitranscriptome.

Biochemistry is fascinating because it tells the story of how our bodies function. It’s hard to imagine why anyone would not want to learn about this! Now is a particularly exciting time to be a part of this field, because we have so many incredible technologies that enable us to study the molecular biology and chemistry of living systems in ways that we never could before.

Kate’s top tip

Follow your passion. If something interests you, pursue it and don’t be deterred if you feel out of your comfort zone.


Associate Professor Sarath Janga
Indiana University Indianapolis

Fields of research: Bioinformatics, genomics, biomedical engineering

While I was studying engineering in India, I undertook a three-month internship in Mexico, where I studied gene regulatory networks in bacteria with Dr Julio Collado-Vides, a computational genomic scientist. This experience inspired me to work as a computational biologist for several years, studying genome structure in bacterial systems during the early years of the genomic revolution. These research experiences paved my path to applying bioinformatics to life sciences for the betterment of medicine.

My lab uses bioinformatics and computational approaches to study RNA modifications. We employ machine learning and artificial intelligence methods to analyse complex datasets resulting from cutting-edge sequencing machines. These new-age sequencers generate a huge amount of data and so require powerful computers to analyse them.

I am proud to have been recruited by NASEM to contribute to the RNA sequencing report. I am pleased that I could share my expertise in computational RNA biology (such as the application of computational methods to study RNA sequences, structures and interactions with other biomolecules in cells) to educate others about the importance of RNA sequencing and its benefits to life sciences, engineering and medicine.

It is essential that we combine biological sciences with cutting-edge technology. The next generation of RNA biologists will need multi-disciplinary skills in genomics, bioengineering, chemical biology and computer science. With these skills, you will be equipped to meet tomorrow’s workforce needs and to discover tomorrow’s medicines.

Sarath’s top tips

1. Develop an appetite for biology, engineering and technology.

2. Seek practical experiences that will allow you to appreciate the biological problems associated with RNA sequencing and that will excite you to develop technological solutions to these challenges.


Dr Nick Adams
Thermo Fisher Scientific

Fields of research: Biomedical engineering, biotechnology

When I was 14 years old, I built a simple contraption to more efficiently route the brake cables on my BMX bike so I could do cool tricks! Later, when I took my first biology class, this realisation that I could make products better was coupled with a fascination with how living systems work, particularly how information is stored in DNA and RNA. This set me on a path to build tools that interface with biology to improve people’s lives. That path was biomedical engineering.

As a systems engineer in biotechnology, my role is communicating across teams of hardware engineers, software developers, molecular biologists, chemists and the business team to ensure that the components of the systems we are developing (instruments that detect, quantify and analyse DNA and RNA from biological samples) will work well together and address our customers’ needs.

My proudest career achievement was discovering a new way to amplify and detect DNA and RNA that was more robust and less expensive than the traditional method. Despite many challenges, I turned that idea into a device that was loved by the local Department of Health and used for flu diagnostics.

The role of industry is critical for driving innovation, particularly in large-scale scientific endeavours. As someone who works in industry, rather than academia, my role in the NASEM committee was to provide insights into how market opportunities motivate and incentivise companies to participate in such efforts.

The promises of biotechnology for improving the well-being of individuals, communities and societies will continue to be fulfilled at the interface between engineering and biology. Leveraging your unique perspectives and skills to improve people’s lives is extremely satisfying.

Nick’s top tip

Take advantage of every opportunity to develop skills and experience. Building bikes and working as a diesel mechanic and an electrician not only made me a better engineer, but helped me decide that biomedical engineering was right for me.


Professor Mary Majumder
Baylor College of Medicine

Fields of research: Bioethics, policy

I studied law, and for several years I worked as a practising lawyer involved in large commercial transactions. Some of these transactions raised ethical issues in light of larger social impacts. I was attracted to the field of bioethics (which includes ethical issues in healthcare and ethical questions related to science and technology) because it provides space to consider ethics and the ‘bigger picture’.

A lot of my work has focused on the ethics of data sharing and privacy. There are benefits to sharing information in a thoughtful and trustworthy way to advance science, but there are also concerns about what might be done with an individual’s data.

While the NASEM report addresses data sharing and privacy, my biggest contributions drew on my policy, rather than bioethics, background. I was involved in thinking about how to get from Point A, where we are now, with some promising developments but so much still to be done, to Point B, a future where the tools and technologies for end-to-end sequencing of RNA with all its modifications exist and are widely accessible.

I think bioethics is inherently interesting to most people because the issues are often linked to challenging questions and compelling stories. For example, what is the line between life and death? What should happen if a family believes a ventilator is keeping their child alive, but doctors believe it is only maintaining a lifeless body? If you find these kinds of questions interesting, you are a good candidate for the field of bioethics.

Mary’s top tips

1. Search the web. There are lots of resources available to help you learn about different aspects of bioethics.

2. Look for internship opportunities with bioethics organizations and departments, which may be clinical (hospital-based) or research-based.

Do you have a question for the team?
Write it in the comments box below and the team will get back to you. (Remember, researchers are very busy people, so you may have to wait a few days.)

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Learn more about how RNA is synthesised from DNA during transcription, and how proteins are synthesised from RNA during translation:

www.futurumcareers.com/an-educational-journey-through-cell-biology