Science Friday - Step Aside, DNA. It’s RNA’s Time To Shine.

Episode Date: June 10, 2024

DNA has long been studied and understood as the genetic blueprint for life on Earth. And related scientific endeavors, like the Human Genome Project, have received enormous attention. But DNA’s lesser-known counterpart, RNA, which translates the instructions from those blueprints into proteins in our cells, has received far less focus.But a lot’s changed in the last few years. The success of the mRNA COVID vaccines has led to a renewed interest in the potential medical therapies for this tiny molecular powerhouse, with applications ranging from CRISPR gene-editing to an mRNA-based cancer vaccine.Dr. Thomas Cech, distinguished professor in biochemistry at University of Colorado, Boulder, and the author of the book The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets, joins Ira Flatow to tell us how why RNA has gotten the shorter end of the research stick for so long, how it could help us understand the origins of life, and why this misunderstood molecule might be the key to a next generation of big scientific discoveries.Read an excerpt from The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets at sciencefriday.com.Transcripts for each segment will be available after the show airs on sciencefriday.com.  Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Why do scientists want to remind you that RNA is more than just part of a COVID vaccine? It's in all of the food that we eat. It's in every living being that we encounter on our planet. It's Monday, June 10th, and you're listening to Science Friday. I'm SciFri producer Dee Peter Schmidt. We've all heard of DNA, the genetic blueprint of life, but off to the site is RNA, DNA's lesser-known counterpart, which helps actually implement those blueprints in our bodies. DNA's gotten most of the spotlight over the past half-scent. century, but that's changed in the last few years thanks to the success of the mRNA-based COVID vaccines, and it's led to a renewed interest in the potential medical applications for this tiny molecular powerhouse. Here's our flato with a scientist who sees a bright future for RNA research.

Here to tell us how we got here and why this misunderstood molecule might be the key to a next generation of big scientific discoveries is Dr. Thomas Chek, distinguished professor in biochemistry at the University of Colorado in Boulder, and author of the book, The Catalyst, R&A, and the Quest to Unlock Life's Deepest Secrets. He won the Nobel Prize in Chemistry for his R&A research in 1989, and I'm happy to welcome you to Science Friday. I'm so happy to be here, Ira. Nice to have you. You know, for a lot of us, our first meaningful interaction with RNA was with the M-RNA-COVID vaccines. As someone who's been studying this for decades, they've been, that also feel like a big moment for you, too?

Well, it was, Ira, and I'll talk a bit about that, but I just need to correct you a little bit, and I hesitate to do that. You said this was people's first encounter with RNA, but actually it's in all of the food that we eat, whether we're meat lovers or vegetarians, it's in every living being that we encounter on our planet. And in fact, here in Boulder, we're, we're We might even say it's organic. Let's talk about then what MRNA exactly is. Tell us. It's a copy of the instructions that are stored in the DNA double helix,

but it's just a copy of one of the two strands. The bits of information in the DNA, as most people know, go by the letters AG, C, and T. And RNA just copies those. it's AGC and U, U in RNA is the informational equivalent of the T that is found in DNA. So once you've got this copy of the DNA alphabet, this message moves out from the cell nucleus into the cell cytoplasm, where it instructs the formation of particular proteins. and if that's all that RNA could do, it would be important. But there are many cooler things that we'll talk about, I hope, in the next minutes.

Well, staying a little bit about the rudimentary knowledge that most of us, we, the public, don't have. When we say RNA helps make proteins, what do these proteins turn into? What do they do for us? Proteins are really the movers and shakers in every cell in our body. So they are responsible as enzymes for digesting the lunch that I just consumed. They allow our muscles to move, and they are responsible for our hearts to beat. They also form the structures of the biggest part of the structures of all of our cells, all living things. So proteins, there are about 20,000 different ones that make up a human.

And proteins are really fundamental to allowing life to exist as it does. Well, let's begin. Tell us about these other things that RNA can do. Right. So there are a lot of RNAs that are called non-coding RNAs because they don't care at all about instructing the formation of particular proteins. Instead, they do things like power the immortality enzyme called telomerase, which keeps our stem cells and our sex cells, our germline cells, active and growing. Unfortunately, it also powers cancer cells.

Then there are RNAs called S-I-R-N-A, small interfering RNAs, first found in a minuscule round. worm, but then found to also be in all the cells in humans as well and have been converted into pharmaceutical agents, which are saving people's lives. And then another area that we could touch on would be the CRISPR genome editing machinery, which derives its incredible specificity, its ability to seek out a particular part of a chromosome to act on due to the fact that it carries around a guide RNA. So those are just a few of a dozen examples of major categories of non-coding RNAs. And let's go back to us meeting MRNA in terms of the COVID vaccine.

If MRNA can be used to fight viruses, can RNA be used to fight viruses, can RNA be used to fight other illnesses we have? Well, that's the big question right now. It sure seems promising. And the COVID-19 vaccines really solved a lot of technical problems that now can be redirected for vaccines and other therapeutics towards other diseases. We're hoping that a quick one might be a flu vaccine that would be much more effective than the rather modest efficacy, typically between 30 and 60 percent from year to year, of the current flu vaccines. And that's because the vaccine manufacturers, it takes so long to make the flu vaccine, believe it or not, a million chicken eggs per year in the U.S. alone are hand injected with an incapacitated flu virus to give rise to the flu vaccine.

So this takes so long that we don't, we have to start the process before we really know which subtype or which strain of flu virus will be around in flu season. Now with the mRNA vaccines, it's so fast to make these that one can wait until you see what kind of flu virus is starting to emerge and then customize the vaccine. That's the idea. And I'm hopeful that that will happen within a few years. What about the big C, cancer? Any hope there? That's really, again, a little bit higher hanging fruit, but I'm very hopeful. At first, when I heard about cancer vaccines, I was confused because we think about vaccines as protecting us against pathogens, viruses, bacterial infections. Cancer is intrinsic to our own human biology gone haywire.

And so how can we possibly vaccinate against that? Well, it turns out that cancer cells are spewing out a lot of mutated proteins. And these proteins are enough different from the proteins in a healthy human cell, that we should be able to train our immune system to be on the lookout for them and to kill any cells that are producing these unnatural proteins, that is cancer cells. That's underdevelopment right now. It's being tested? It's in clinical trials. The first readout, it's a collaboration between Moderna and Merck.

And I have to disclose that I was on the board of direction. directors of Merck for a dozen years. So I've heard about this, but it is public knowledge, too. You can find it on the internet. And it seems hopeful. Speaking of hopeful, let's talk about CRISPR. You brought that up a short while ago, CRISPR using RNA as a guide to precisely target and modify DNA sequences. What kinds of benefits might we get from that? The first CRISPR therapeutic was actually approved both in the UK and then in the United States late last year. So just a few months ago. And this was against the incredibly debilitating disease, sickle cell disease, particularly prominent in the African American population. So the ability to allow these people to not have a sickle cell

crisis where their red blood cells distort into this sickle shape and clobiles. clog up their capillaries, incredibly painful, prevents, you know, moms from being able to take care of their kids and hold down a job. This could be a wonderful thing. But the boundaries of this are huge compared to just sickle cell disease. So many other diseases like muscular dystrophy, cystic fibrosis, enormous number of diseases where we know the genetic cause. We know which letter in the DNA alphabet is misspelled. But now, with CRISPR, we can actually do something about it. In your book, you say that around three quarters of the human genome consists of dark matter RNA with unknown functions. Now, I love this comparison because I used to bring this up with physicists

who talk about dark matter in the universe, we don't know what 96% of the universe is made out of. What about this dark matter? What do you mean by that exactly? And what kind of breakthroughs to you anticipate happening here in the dark matter in the RNA version? Thank you for that, because it is fascinating that three quarters of the human genome is not copied into messenger RNA, but is copied into these non-coating RNAs. The jargon term for these is link RNAs or long non-coating RNAs. Different ones are produced in the skin cells, in the liver cells, in neurons, in the brain, in the heart muscle.

So they tend to be very tissue-specific. In any one tissue, you would not see all 75%. of this dark matter being converted into RNA. But if you add up what all of the tissues in the human body are able to produce, then you see that most of it is made into RNA in some tissue or another. But the dark RNA must have some usage, right? I mean, or else it wouldn't be conserved, I'm guessing. Well, some of us would agree with you.

However, I have friends who are scientists who think it's all, junk who think it's noise that... We used to say that about junk DNA, didn't we? Well, this is the junk. This is the junk RNA made from the junk DNA, right? So if you believe in the junk model, you say, okay, junk DNA makes junk RNA. Let's throw it away. And of course, that's what the cell does.

RNA is not nearly as stable as DNA. That's why we isolate DNA from the woolly mammoths that are encapsulated in glaciers in Siberia. We can't get RNA out of those ancient cells. So maybe it's just being made and thrown away. It's just like life isn't perfect. Stuff happens. You get rid of it. Or we just haven't discovered yet what it does.

That's what I think, Ira, because many of the non-coding RNAs like the, the telomerase RNA, for example, these CRISPR guide RNAs, these small interfering RNAs. Before we knew their function, they would have been part of this dark matter and they would have been branded as junk. Right. I get it. I know that you and others theorize that RNA might have come before DNA in terms of getting life started on Earth.

Fill us in on that. Well, this is a fascinating outcome of our. initial finding that RNA could be a bio-catalyst, RNA with enzyme-like properties. And if you think about how life could have started almost four billion years ago on the primitive earth, you come up with the sort of mother-of-all chicken and egg problems immediately. And that is, in order to have life, you need to have some kind of an informational molecule to be passed down to the next generation. That could be DNA. But DNA doesn't do anything. It just sits there. It requires protein enzymes to copy the DNA and make daughter molecules out of the mother molecule. So to be passed down to the next generation. So how could this have

happened four billion years ago? Do we really believe that in the same droplet of water at the same time by random chemical processes that DNA and a machine that could copy that DNA, protein enzyme could have occurred at the same time seemed really high hurdle for the start of life. Now that we know that RNA, that ribonucleic acid, can be both an informational molecule, again, hearkening back to the SARS-CoV-2 virus, just uses RNA. So RNA can be an informational molecule, but it can also be a biocatalyst, and it can assemble the AC, G, and building blocks into larger molecules, maybe at the beginning there was just RNA copying itself. And the proteins and the DNA came along later.

Wow. I love to hear this kind of thinking. Last question. You wrote in your book that originally you were, quote, a DNA guy, but then you switched to RNA. Do you think it made the right choice there? It's been good for me. Well, why did you make that choice? Why did you switch? Did you really recognize early on that? This is really good stuff. It was serendipity, which was, I think, best defined by Winston Churchill, who is said to have said, many a man stumbles over the truth, but most get up, wipe themselves off and hurry on as if nothing had happened.

So we stumbled over a case where the DNA was being made into an RNA that was rearranging its own internal structure. It was cutting and splicing itself. And that was worth investigating because this fact that RNAs underwent splicing, and in humans, especially, this is just rampant, that RNAs are cut and rejoined after they're made. but everyone knew this was happening, but no one knew the mechanism. And as a biochemist, I wanted to understand how it happened. And so that's what encouraged us to switch from being DNA researchers to RNA researchers and ultimately to find this first example of RNA catalysis. Well, I think you made the right choice, Dr. Check.

And I want to thank you for taking time to be with us today. It's a great book. Thanks so much. Dr. Thomas Chek, Distinguished Professor in Biochemistry, University of Colorado and Boulder, and you can read an excerpt from his new book, The Catalyst, R&A, and the quest to unlock life's deepest secrets. That's at ScienceFriday.com slash RNA. And that's it for today.

Lots of folks help make the show happen, including Felissa Mayors, Kathleen Davis, Jordan Smudjick, Charles Bergquist. Next time, how the author of classic science fiction stories also wrote the military's textbook on SciOps. Join us. I'm SciFri producer, D. Peter Schmidt.