A Road Map for a New Era in Biology and Medicine
Most people are familiar with DNA, but its cousin, RNA, has become widely known only recently. In 2020, of course, RNA was in the news all the time: the COVID-19 virus is made of RNA, as are the vaccines to combat it. Technologies based on RNA could lead to innovations in biology, medicine, agriculture, and beyond, but researchers have only scratched the surface of understanding what RNA is capable of.
A new report from the National Academies, Charting a Future for Sequencing RNA and Its Modifications: A New Era for Biology and Medicine, proposes an ambitious road map for coordinated projects to understand RNA. This large-scale effort is inspired by what was achieved for DNA two decades ago by the Human Genome Project.
On this episode, host Monya Baker is joined by Lydia Contreras, professor of chemical engineering at the University of Texas, Austin, and one of the authors of the report. Contreras talks about what RNA is, the challenges and potential of this effort, and what lessons could be learned from previous efforts with the Human Genome Project.
Resources
- Read the full National Academies report: Charting a Future for Sequencing RNA and Its Modifications: A New Era for Biology and Medicine.
- Visit the Contreras Research Lab website to learn more about Lydia Contreras’s work.
- Retrospectives on the Human Genome Project.
Transcript
Monya Baker: Welcome to The Ongoing Transformation, a podcast from Issues in Science and Technology. Issues is a quarterly journal published by the National Academy of Sciences and by Arizona State University.
If you’re like most people, you’ve heard a whole lot more about DNA than about RNA, DNA’s more dynamic, less stable cousin. But in 2020, RNA was in the news all the time. The COVID-19 virus was made of RNA. So were the vaccines that taught our bodies how to combat it. Technologies based on RNA could bring more innovation in medicine, agriculture, and beyond. Still, science has barely begun to catalog what RNAs occur in what tissues and under what conditions?
Earlier this year, the National Academies put out a report called Charting a Future for Sequencing RNA and Its Modifications: A New Era for Biology and Medicine. The report proposes an ambitious roadmap for coordinated efforts to understand RNA.
My name is Monya Baker. I’m joined by Lydia Contreras, a professor at the University of Texas, Austin, and one of the authors of the report. Lydia tells us what RNA is, the challenges and potential of this effort, and what lessons could come from the Human Genome Project, the pioneering large-scale effort that was completed two decades ago.
Lydia, welcome.
Lydia Contreras: Thank you, Monya. It’s exciting to be here today.
Baker: Tell me a little bit about yourself. How did you come to study RNA?
This must be the hottest and coolest area of biology to study.
Contreras: Science was always my favorite subject since I was in middle school. I loved science, loved biology, chemistry. In college, I have my background is in chemical engineering with a concentration in biochemistry. So I always had a fascination of how biological molecules function, how they work together, and I think it really hit on RNA a summer that I spent abroad. It was 2009 and it was the year where the Nobel Prize in Chemistry was awarded for studies of structure and function of the ribosome. This was to Dr. Ada Yonath and Thomas Steitz and Venkatraman Ramakrishnan. And that year I was lucky enough to hear a talk by Dr. Yonath on ribosomes and just to hear, see the molecules. These are 3,000 base pairs of RNAs intertwined with proteins producing something that was so useful to the cell and hear the story was fascinating for me that summer. And I really realized how open widely the field of RNA was that I was just looking at one out of many, many RNA molecules. And I think that was the summer that I said, “This must be the hottest and coolest area of biology to study.”
Baker: That’s great. Yeah. RNA is such a complex machine. But before we get into talking about RNA, one thing that I found really interesting and inspiring is that you’re really committed to outreach. Tell me more about that.
Contreras: So I grew up in an environment where… Thinking back, I think there were many students, many young students that would’ve been great scientists, but those were not careers that we were aware of in general. We were not told about science. We were not had open discussions about discovery and how that could really make an impact. And I think it’s harder to see relative to other professions where you see people all the time and they’re visually community leaders and helpers. And I think other professions have done a better job personifying and giving emotions and bodies and faces to what they do.
So a big commitment for me once I started having my own lab, doing my own research was really community awareness. I really get excited when I get opportunities to bring a little bit of awareness about scientists, how much of different things scientists do, what the profession is about, and using that excitement to really promote new individuals and new people coming into the field. I think that we need a new generation to get excited about these new things. And of course, we’re going to need a whole new labor force that is really trained on these issues and creative ways to build our capacity in these areas to be competent technologically around the world. So that’s a big thing that really drives my excitement of being in committees like this.
Baker: Tell me just a little bit about this committee that you were a part of. What were you called to do?
Contreras: So this was a committee, that was the meaning a group of scientists came together. It was about 16 in different fields, and this was put together by the National Academies of Science and Engineering and Medicine. And the goal of the committee, what we were called to do, was to discuss opportunities and challenges having to do with the initial discovery, initial studies that have been emerging more and more on this concept of the chemical varieties of RNAs that actually exist in nature. This committee was actually a follow-up discussion of another committee that in 2022 was led by the National Institute of Health by Dr. Fred Tyson, where the need to really come in early to expand on questions that had to do with, “How do you capture all these vast of RNA sequences that now we know are there and the diversity of all these sequences of RNAs? How do we capture that? How do we study? What does that mean?”
How do we integrate these in the classroom, change the curriculum, build a workforce? And ultimately how does this change the world?
This committee got called to do a more in-depth study of those questions by the National Academy and involving, again, people in academia, in the industry as well as a great staff there that led a lot of these discussions and interactions. So questions that we were called to think about were: “What is really this chemical diversity of RNAs that we see? How are we finally going to get to this? How is this data going to be stored, storage, maintaining it? Who’s responsible? How do we inform the public? How do we create awareness? How do we integrate these in the classroom, change the curriculum, build a workforce? And ultimately how does this change the world as far as technology, agriculture, medicine, health, et cetera.” So there were a series of very in-depth studies that went into each of those areas. It was fascinating to be part of this group.
Baker: It reminds me of what I understand from the Human Genome Project where it was years of meetings before this thing actually started. Let’s back up a little bit and let’s talk about RNA. What does this mean? Chemical diversity of RNA and RNA and DNA they’re very different molecules, right?
Contreras: Absolutely. Most people recognize DNA as a very stable blueprint that is in every single organism to dictate, “How things go? What molecules get produced? What proteins are made, et cetera.” So when it comes to RNA and DNA, both are nucleic acids, but their key differences that really get to the functional differences as to why RNA is so versatile, easy to manipulate, and has caught so much excitement lately. So RNA it’s usually one chain, typically single-stranded versus DNA is typically double-stranded. So there’s two chains intertwined that makes the molecule pretty stable. So that means that for RNA, there’s these large spaces or grooves that form which give it a lot of dynamics in terms of molecules interacting with it, being able to degrade it, being able to make it more stable, et cetera. So as I said, DNA it’s really genetic storing information, but RNA can convert that information and make it dynamic.
What’s important is that RNA becomes then a lot more reactive than DNA, easier to manipulate, and you can change it around without necessarily affecting permanent changes to the cell.
So that’s what’s really exciting is that it can read DNA, but then depending on what’s going on in the cell on environmental factors and the type of the cells, it can make it dynamically and it moves around in the cell. So it’s not contained to the nucleus like DNA, but it leads to different locations outside of the nucleus. And so what this turns out, with the addition, that RNAs tend to be shorter molecules. DNA, if you really think of DNA, when you stretch it out could be several centimeters long, but RNAs can have a variety of sizes. There can be many as small as tens of nucleotides, which is tiny, to a few thousand, so they are much smaller. What’s important is that RNA becomes then a lot more reactive than DNA, easier to manipulate, and you can change it around without necessarily affecting permanent changes to the cell. So you’re not affecting that blueprint.
So when we talk about this versatility of RNAs, we’re talking about the types of RNA molecules because RNAs get formed by this process called transcription. They make several different molecules and excitingly in many different flavors that can have many different chemistries depending on environments, cell type, organism, and that’s what we refer to as this repertoire of RNAs in the cell.
Baker: I’m old enough that I remember the Human Genome Project and I remember how surprised people were at how few genes’ humans actually had. It’s not necessarily the DNA, it’s all these things that the RNA can do and that makes this project to understand RNA, I think a lot more complex. So in terms of getting a comprehensive understanding of RNA, what are the biggest differences between that goal and the Human Genome Project?
Contreras: I think it’s important to first highlight the similarities of the two projects and the goals and ways that they were similar. So I think both goals are to get this more complete understanding of the repertoire of sequences. And in both projects, I think it was this recognition that this was underexplored and that this would be critical for advancing basic knowledge of every single living system for manipulating health, humans, plants, animals, preventing disease, improving crop yields, stimulating economies.
Where this could be a lot more complex is in the fact that you have to imagine that for every DNA sequence that encodes the gene or information in terms of this blueprint, there are multiple and multiple and multiple RNAs that can be synthesized of different sizes of different chemistries. And that is also dynamic depending on the cell type, depending on where it goes to the cell, depending on the timing that it gets synthesized on the age, on the level of stress. So this is hugely far more complex as opposed to the genome that we can say even for one organism, there is a vast number of multiple RNA sets that can be present depending on the time. So this is where the complexity really arises is in the vast repertoire of RNA types and chemistries that can be derived from even one piece of DNA. So not to say that DNA cannot be chemically changed, but for example, we know on the order of 17ish or so DNA modifications, for RNA is almost 200.
Baker: There is so much more to understand about RNA than DNA. It seems to me are there even experimental techniques to understand all those chemistries and all those shapes and all those different lengths of sequences?
We don’t have the tools or the infrastructure, the technology to even get at this question of characterizing this vast repertoire of RNAs that we know exist.
Contreras: The answer is no. And the other answer is that most of the techniques that are out there, you have to extract RNA out of the cell which at that point raises the question of, “What does the real biological molecules look like?” So a major conclusion of this project that we did, of this committee, was the fact that developing technologies and infrastructure to enable exactly that, the understanding of all these types of RNAs in the cell, their function, who are they, where are they and their chemistries is probably the most impactful goal that we can have in the near future. So the answer to your question is really “No.” We don’t have the tools or the infrastructure, the technology to even get at this question of characterizing this vast repertoire of RNAs that we know exist.
Baker: And I know there’s a lot of people working on that. Assuming that there are techniques to characterize the RNA molecules, is there a good way to store the information and share the information?
Contreras: We spend so much time discussing data. We spend so much time discussing even the fact that there are clear guidelines that are needed to deposit data, to store data, to exchange robust and sustainable data, and to create platforms that are maintained, that are up-to-date, that are curated where RNAs are indexed. There is not such coordinated infrastructure yet, and the committee spend a lot of time drafting recommendations where it calls for people to have a coordinated effort to do this. It boils down to needing sustainable, funded, something centrally managed where you can access that information and that is maintained. Those resources are not currently things that we have available.
Baker: Somebody told me a story that when they started the Human Genome Project, people would need to get DNA, run a gel, keep the gel in a freezer for three days, and then you were lucky to get 100 base pairs, which is not the way to get a sequence of 3 billion sequences. So there’s precedence for starting a project before the necessary technologies exist because you’ll learn on the way.
The publication pipeline and timeline is so long that we want to access information quickly.
Contreras: A major issue that we have also in the field is this issue of developing standards. And so standards are key guidelines that we use when we run experiments as to how experiments are done so that we can allow the orange to orange, apples to apple comparisons when results are obtained by different labs using different techniques and methods so that you can actually validate and benchmark results. And so these efforts really should be highly coordinated and standardized so that as we decipher all this information, there’s less risk for being misled. The publication pipeline and timeline is so long that we want to access information quickly. So I think it’s definitely worth discussing data and data sets separately from waiting on that timeline that it takes to have completely published stories and results as long as we really work on strict guidelines and standardized ways to report and share.
Baker: I also wanted to ask you about the norms of data sharing. And my understanding is that when the Human Genome Project started, people wanted to keep their data until they had a publication and there was a very hard-fought agreement to release data almost on a daily level. And because they came to this agreement in Bermuda in the off season, these are called the Bermuda Principles. As an aside, there’s all these hilarious pictures of people in khakis and closed shoes lying on pool chairs. So it’s a bunch of people getting together talking about stuff and changing the norms to advance science. And I wonder what has to happen in RNA for that kind of progress to happen?
Contreras: Well, I can tell you that a lot of discussions happen about this, but not in Bermuda, not in any fancy island, not with any khakis and Hawaiian T-shirts. I think there’s been a big push in science overall for more openness and more readily publication of results. So before most of the papers would really wait for peer reviewed for you to have the perfect results and be reviewed, and then reviewers would come back with questions and you would do more work or experiments and return the paper again, and then the paper and the results can see the light. It’s more and more trending now that there is this decision to put results on public archives, immediately, before they’re even published. And so that the community can have access to data, to information, to things that are being done, and speed up hopefully the exchange of information.
So that might be something that really benefits these efforts on RNA, just the general trends in science to be more open with data more quickly. The concern is the same. The concern is making sure that in that model, we still have standardized ways of sharing that information. And this is, I think, one of the issues that’s being brought up is this whole idea of abandoning carefully curated databases and the risk that we take in limiting, at the end of the day, growth and real understanding and effort. So I think the balancing of those things is going to be important. The speed at which data is shared, the openness with the community, in a way that has some control for standards.
Baker: It just seems like such a tall order. And then making it even taller and more complicated is that in order to have equipment that can get this information about RNA chemistries and sequences, industry is going to need to be involved. Also, industry is going to need to be involved for some of the applications of using RNA and agriculture and medicine. Industry’s going to need to feel like there’s a pathway for them to develop and sell products. And I’m wondering how all of that plays into the need for standards and openness?
Contreras: So the nice thing here is that there’s a huge incentive for industry to jump in. There’s a huge need to develop reagents so that we can go into the lab and study these processes fundamentally and basically. There’s a new need to create ways that we can synthetically construct a lot of these molecules so that we can exploit them in the development of medicine, in the development of drugs. One example of this is the way we were able to synthesize mRNAs during COVID-19. So that saved the day to make an mRNA vaccine. So that’s a classic example. If you think about that industry that’s emerging when it comes to even mRNAs in health and as biomolecules that can be for medical purposes, there’s a huge incentive. There’s a huge incentive for developing technologies because there’s so much that we’re going to have to do and pay for these services just like we pay for sequences now after a lot of the results of the human genome sequence.
Industry will need a trained workforce, new people coming in that from the classroom can start learning the value of RNA science, how to do these technologies and getting interdisciplinary training so they can come and promote our workforce in this area.
So I think there is an incentive there in terms of the commercialization on a lot of this, but I think what’s important about what you’re asking is that there’s really a need for everyone to participate to make this growth. So one of the conclusions of the report is that for us to be able to enable this level of innovation that we need, we really need to completely understand the repertoire of this synthesis. There are chemistries, and this needs to be a largely coordinated effort. As I said, we need reagents from industry. We need technologies from collaborations between industry, government, the academy, and those efforts will be really successful, especially if they can be aligned by federal agencies.
So I think that these partnerships will be key when it comes to supporting research in labs, fundamental research, prioritizing these gaps in technology, synthesizing standards. We’re going to have to synthesize these molecules and use them to interpret results. But also, one of the other things is training the workforce. Industry will need a trained workforce, new people coming in that from the classroom can start learning the value of RNA science, how to do these technologies and getting interdisciplinary training so they can come and promote our workforce in this area. So I think there’s several interests that make this partnership have mutual excitement about working together.
Baker: I am reminded of how you became inspired to study RNA because of the work on ribosomes, and I’m thinking there’s a whole generation of scientists who have seen very recently the world shutting down because of an RNA virus and getting safer because of an RNA-based vaccine. So there should be a lot of people that really want to work on RNA.
Contreras: It’s a huge opportunity for the field, and the committees spend a lot of time talking about how do we capitalize this? How do we make the tragedy of the pandemic and the scientific successes that we’ve seen because they’ve been working on these technologies for years? How do we bring awareness? How do we get a whole new generation of people excited in these questions and change the classroom curriculum, incorporate a lot more RNA science?
There’s definitely the public interest, Monya, and I think it’s a great time for us to capitalize that awareness and that collaboration with our entire community to get excited about potential impacts of this type of science.
Baker: I want to read another quote from the report, and it has a lot of technical words in it, but the vision is eye-popping of what the goal is. Tell me about what the situation is now and what’s envisioned.
“If the recommendations are followed, the committee envisions that within 15 years, affordable oligonucleotides of any custom order sequence, length modification, stoichiometry, and structure could be readily available for research and technology development.”
Contreras: This definitely speaks to this huge grand vision that with increased technology and understanding of what the vast repertoire of RNAs look like when they’re in the cell, we can achieve additional capabilities that would allow us not just understanding, but building these molecules synthetically to explore their potential in medicine, technology, synthetic biology, and even for allowing a lot more detailed studies that touch on the functionality of this vast set of molecules. So I think this is what this is really speaking in here. It’s really the potential of what this field can really achieve.
This could be a really powerful technology that can emerge from this level of understanding.
And specifically, when it comes to this custom order idea that you could have the ability just like we do for DNA now. For DNA, now you can envision a sequence and we have figured out now how to synthetically make them, and not just synthetically make them, but synthetically, throw them in a living system so that that living system can have a new synthetic blueprint of what we want that organism or that living system to do. So if you can imagine that with as many more diverse molecules, with as many more diverse chemistries and combinations of that chemistry and length and where they can go, this could be a really powerful technology that can emerge from this level of understanding.
Baker: This report is coming out after the completion of the Human Genome Project, after the completion of a lot of other big science projects. How has the fact that these other big science projects have been completed changed, how people can go about grappling with RNA?
Contreras: I think what we learned from the Human Project was really the potential of how much coordination of efforts across different disciplines and across different sectors can really help to build infrastructure and technology that can quickly pick up to ask a number of questions that we’re not even imagining right now. So along with the human genome, we’re still capitalizing from the Human Genome Project. We’re still spinning off to now know about sequencing microorganisms. So now we’re talking about organisms that live within humans and what are their sequences and talking about microbiomes on all aspects of the earth around us.
So I think that project has had major ramifications on problems that we couldn’t really even imagine that we would be able to solve back when the project started. I envision that something really similar can happen with the level of impact that this RNA sequencing project can have. So I think what we have really learned is how the needs, what it takes to pull something like this off such a complex project. Again, the coordination, the technology, the databases, the openness with data, the standards, and I hope that those are lessons that can really be translating so that we can develop technology that can allow us to do this.
Baker: What would you like to see happen over the next year and over the next decade?
Contreras: I think it will be really nice to have some high-level coordination of how this is going to happen. I like to see some of our governmental agencies really champion some of these efforts that bring together academia, bring together industry, bring together government, and really coordinate this high umbrella of efforts that we’re going to need. We have discussed, again, the need for data organization and sharing. We have discussed the need for technology, which is a major one. We have discussed the need for organizing all these resources, training a new workforce, motivating, making the public aware, and I think we’re going to need people from all sorts of walks of life to really come together and realize the potential, the excitement, but also how they can contribute. So we’re talking, yes, CEOs and companies, we’re talking directors of agencies, but we’re also talking schoolteachers and parents at home, and we’re also talking about your general neighbor that can really understand the impact that these type of technologies can have even so far with a little bit that we’ve known.
And again, I go back to some of the examples of the pandemic, but there are drugs being developed right now that are using chemically change RNAs that are on the pipeline. So this is a huge frontier for our generation that everybody can contribute to. So what I like to see is that effort at the level that is highly coordinated and organized so that we can really move this field forward. I think that the small, single lab, isolated efforts or the big companies that are working with this together isolated without much communication with the rest of the sectors, I don’t think that’s going to be how we’re going to get to the answers as quickly as we can.
Baker: So it’s all about organizing people and effort.
Contreras: Absolutely. And I think that’s one of the big lessons of the Human Genome Project.
Baker: Thank you so much for talking with me. And thank you for all the work you do that’s not strict science, but that helps broaden the community.
Contreras: Well, I think that definitely if we can create more young people that can dream about seeing themselves in the shoes of a scientist and building something that can change the world, I think we’ll have a lot more people put in the effort, the time, and the energy into these type of careers. It’s super rewarding. And I thank you for giving the opportunity for more people to hear about what we really do behind the scenes and how exciting every day can be with any new little thing that you learn, that you know nobody else in the world has figured out, but that one day it’ll be part of a puzzle that would really have a huge impact around the world. I think that message really needs to get out to all of our students.
Baker: Check out our show notes to find links to other resources, including the report, Charting a Future for Sequencing RNA and Its Modifications.
If you’re listening to this, you’re probably passionate about science policy. Please visit issues.org/survey to participate in our survey of the science policy community. And please subscribe to The Ongoing Transformation wherever you get your podcasts. Thanks to our podcast producer Kimberly Quach and our audio engineer Shannon Lynch. My name is Monya Baker. Thank you for listening.