Into the Impossible With Brian Keating - Life's Catalyst: RNA with Thomas Cech [Ep. 423]

Episode Date: June 4, 2024

Join my mailing list https://briankeating.com/list to win a real 4 billion year old meteorite! All .edu emails in the USA 🇺🇸 will WIN! How did life begin? What makes us human? Why do we get sick and grow old?  For more than half a century, we've searched for answers to these questions in DNA. But after a series of groundbreaking discoveries, attention has turned to RNA, the long-overlooked molecule that is now at the heart of biology's greatest mysteries. Here today, to shed light on this topic, is none other than the Nobel laureate Thomas Cech. Thomas shared the 1989 Nobel Prize in Chemistry with Sidney Altman for their discovery of the catalytic properties of RNA. He discovered that RNA could cut strands of RNA itself, suggesting that life might have started as RNA, and found that RNA can not only transmit instructions but also speed up the necessary reactions.  His upcoming book, The Catalyst, promises to bring years of pioneering research to the forefront, demonstrating how RNA holds the key to understanding life on Earth—from its very origins to our future.  Join us as we explore the most transformative breakthroughs in biology and beyond on this episode of Into the Impossible!  Key Takeaways: 00:00 Intro 01:17 What is life? 02:05 Judging a book by its cover 05:44 Does profit drive innovation?  10:51 The RNA breakthrough  14:40 Is DNA a one-trick pony? 24:54 Panspermia, DNA and RNA 29:25 RNA’s role in the end of life 37:01 CRISPR  42:09 Are DNA and RNA the only two informational molecules?  46:57 The future of education  51:38 The greatest thing humans have ever done 53:08 What Thomas has been wrong about 54:22 Outro — Additional resources: 📝 Get one month of Snipd Premium for free with this link: https://get.snipd.com/Cx7S/brianSnipd Snipd lets you take Smart Notes 🧠 with AI 💡 — it’s my favorite podcast player 😀 ! ➡️ Learn more about Thomas Cech: 💻 Nobel Prize: https://www.nobelprize.org/prizes/chemistry/1989/cech/facts/   📚 Get The Catalyst on Amazon: https://a.co/d/9oaErgg ➡️ Follow me on your fav platforms: ✖️ Twitter: https://twitter.com/DrBrianKeating  🔔 YouTube: https://www.youtube.com/DrBrianKeating?sub_confirmation=1  📝 Join my mailing list: https://briankeating.com/list  ✍️ Check out my blog: https://briankeating.com/cosmic-musings/  🎙️ Follow my podcast: https://briankeating.com/podcast Into the Impossible with Brian Keating is a podcast dedicated to all those who want to explore the universe within and beyond the known. Make sure to subscribe so you never miss an episode! Learn more about your ad choices. Visit megaphone.fm/adchoices

How did life begin? What makes us human? Why do we get sick, grow old, and eventually die? For more than half a century, we searched for answers to these questions in DNA. But after a series of groundbreaking discoveries, attention turned to a more miraculous molecule, RNA, the long, overshadowed molecule that is now at the heart of biology's greatest revolutions. Here today, to shed light on the secrets of life and unveil the RNA, age is none other than the Nobel laureate Thomas Chek. Tom shared the 1989 Nobel Prize in Chemistry with Sidney Altman for the discovery of the catalytic properties of RNA. His new book, Out Today, The Catalyst promises to bring years of pioneering research to the forefront,

demonstrating how RNA holds the key to understanding life on Earth, from its very origins to our future. Join us as we explore the most transformative breakthroughs in biology and beyond on this impossibly. lifelike episode of Into the Impossible. Let's go. Any sufficiently advanced technology is indistinguishable from magic. Open the pod bay doors, how? What is life? So life is reproduction and evolution. In order to be a living being, you have to go from one generation to the next. But if you do that perfectly, if you just transfer information, without any alteration, then you can never evolve beyond the most simple and primordial of organism.

So you have to have some mutation in there. We think of mutation as a bad thing, and it can be if in the wrong place. But having a little mutation during the copying of informational molecules is what allows systems to achieve a higher plane of existence. And in the book called The Catalyst, which we will now dive into doing my famous world-renowned presentation segment called Judging Books by Their Covers, where I will ask you to take the listener and viewer on a journey through the title of the book, the subtitle of the book, and this mysterious mesmerizing cover art that I claim that you will know more about than anybody that's listening. So, Tom, take us through and help us judge this book by its resplendent cover. So the main title is the catalyst, and that has many layers of meaning. My incentive for writing this book was to try to catalyze some public interest in exciting scientific topics, to try to reach to the non-scientists.

So there's that kind of catalysis. There's also the fact that RNA has been a mover and shaker in living systems in really some. fantastically and unimaginably exciting ways, which I'll talk about. And then in the most personal way, our laboratory was the one that found that ribonucleic acid RNA had biocatalytic activity. So that's the most, the smallest meaning of catalysis for the book. And the artwork, it looked to me like perhaps a singularity, which oddly enough, This book has more physics and cosmology, which delights me as a cosmologist, I have to say, than I was expecting. In fact, it begins with cosmology and it ends with dark matter.

I wanted to ask you, the artwork does it represent a black hole, a singularity of information overload as catalyzed by RNA or something else? Brian, the explanation you just gave is the best one that I've heard, so let's just go with it, okay? All right. The follow-up, I expect, you know, co-authorship. I've only written one book with a Nobel laureate, so this will be great to have. have a second one on my resume. Tom, you described RNA for many years as sort of being the drone to DNA's queen. And it made me think, what are we kind of neglecting or overlooking now in your field and your field of biochemistry and broadly science of life? Are there things that

we are overlooking that have the potential for revolutionary transformative powers the way that RNA has, maybe even exceeded? I'm going to make the case, maybe you'll oppose it, but that RNA is more interesting than DNA. Maybe you agree, maybe you're not. But what are we overlooking right now? I'm not sure we're overlooking it, but we're right at the cusp of having to come to grips with the fact that AI and machine learning can really solve a lot of daunting problems in biology, understanding living systems that we've struggled with for, you know, a century or more. And my colleagues do not like that. to hear this. Experimental scientists are extremely disappointed to think that we may be just sitting in

front of computer terminals in the future, but it's already starting to happen with the new release of Alpha Fold 3, the fantastic work that David Baker is doing in Seattle, calculating molecular interactions. We still need to do experiments to to, to, to, test those ideas, but I think the time will come when the machine learning is going to take over. And that's a bit sad for those of us who are experimental scientists. Yeah, you talked in videos I've seen about your favorite experiment and the joy of being in the lab frequently comes across in your work. And typically we hear more about the theorists, the, you know, the Einstein's or the, you know,

the Feynman's. We don't get the chance to really have a hands-up. on look, the people doing the hands-on research that without which we wouldn't have such brilliant theorists to have full employment. When you mentioned alpha fold, I was going to save this towards the end because you talk about, you know, DNA or sorry, RNA's past, it's present and its future. I was going to ask you in the future segment, but I'll just ask you now. Alpha fold, as I understand it, has been transformative, revolutionary.

It can, you know, sequence all sorts of things and look at foldings of proteins, which, you know, if you had told me that folding is so important, as a kid, I would have, you know, and bed in my bed more often than I actually did. But Tom, tell us, why is it concerning or should it concern us or not? That AlphaFold is actually a for-profit entity. And in fact, a lot of what they're producing, the CEO is just invested and started a private equity fund or something like that to the tune of $100 million or so. Should we be worried about this powerful tool that scientists are using and legitimately so,

but it also has a private side, which is for-profit, there's no doubt about it? So should we be worried? Scientists are frustrated and disappointed by the fact that we don't have access to the code in alphafold. So we can't really either understand some of the parameters, some of the limitations of the algorithms that are being used, nor can we, with the kind of open software that we always publish, other people can go in and they can alter it to tune it to their particular needs and problems and questions that they want to answer. So that's certainly a for the moment a disappointment. On the other hand, I would say that for-profit companies can drive innovation

and people who need to find a way to make a profit. This is a one reasonable way. I mean, just as pharmaceutical companies, after they spend hundreds of millions of dollars testing a pharmaceutical compound, can't afford to give it away for free, although they often do to the third world, but they can't afford to give it away for free to everybody or they'd be out of business. So there's always this sort of knife edge on the one side. Open access and free use is what we believe in in academia, but on the other side, we can understand that a lot of goods have to be sold for a profit. Hey there, do you want to dive deeper into the minds of Nobel laureates, billionaires, and astronauts

and acclaimed authors and science and technology? Of course you do. And now you can't. Just join my Monday Magic mailing list at bryanketting.com slash list. And you'll not only receive the latest and greatest news in the world of STEM, but you also have the chance to win a real-life meteorite, a fragment of the. early solar system. Who knows? Maybe a meteorite just like this brought life to Earth in what's called panspermia. So join up, Briankeating.com slash list. And if you have a dot edu email address

and you live in the United States, you're guaranteed to win one. For those of you lucky students, faculty, postdocs, and so forth, go to Briankeen.com slash edu. Now, back to the episode. What is a catalyst? And keep in mind you're talking to a cosmologist. And what was the experience like? What was the pivotal moment when you first realized that RNA had catalytic properties? A catalyst in chemical sense is an entity that speeds up a transformation, a molecular transformation, like a chemical reaction. So it could speed it up by often a billion-fold or a trillion-fold or more. So we're not talking about small peanuts here. We're talking about big increases in rate.

Now, biological catalysts do that, but they have an additional feature that is typically missing in chemistry, and that is incredible specificity. So they catalyze or speed up the rate of one particular transformation without touching anything else off to the left or to the right. And we'll talk about probably CRISPR genome editing a little bit later. And so using that as an example of catalysis, out of the million pages worth of text in the entire human genome, the CRISPR genome editing machinery can find one sentence, and then it can make a change on one letter in that one. sentence. And so that's the kind of catalysis that gets us excited in biology.

What was it like, the pivotal experiment, when you first discovered this potential for our RNA to act as a catalyst? So we were studying a pond scum organism, a single-celled animal called tetrahimina, and we were studying it because it had 10,000 identical copies of a particular gene. And if you're a biochemist, having lots of stuff to work with is a real advantage. Most of the genes in humans are present in two copies, one from mom, one from dad. So having 10,000 copies per cell seemed like a real, you know, foot in the door making some discoveries. What we found early on was that this gene was interrupted by a stretch of nonsense, called an intron.

And this is, you could relate this to your favorite film being interrupted by a commercial message. You would just like to fast forward through this thing. Well, the cell doesn't have a way of fast forwarding through these introns, but what it does is it splices them out at the level of the RNA copy of the DNA. So it cuts out the left end of the intron, it cuts at the right end of the intron, and it stitches those two places together to make a useful RNA product. Now, this had been discovered just a few years before I started my lab in Boulder. So when we found what was perhaps the hundredth example

of an intron, it wasn't that much of a discovery. But here we had an organism that was doing 10,000 genes worth of this process every second. And so we had a a lot of material to work with. So we thought maybe we could figure out what everybody wanted to know, which was the mechanism, the nuts and bolts. How does this splicing work, given that the cell doesn't have a remote that it can do fast forwarding with? So what we found early on was that it was very easy to get this reaction to go in the test tube. And getting a reaction to go in a test tube is the first step towards understanding the catalysis. You know, what is speeding up this reaction

and giving it such extraordinary specificity? By specificity, I mean that exactly the same two positions along the RNA were being cut and rejoined every time it happened, and that was important for it to be biologically active. So we were trying, the reaction was working almost spontaneously, and we thought, well, where's the catholicially? power that is driving this. It was known since James Sumner's Nobel Prize 50 years earlier that all enzymes are proteins. So there must be some protein that was responsible for this RNA

splicing. So we were looking for it, but no matter how much, how stringently we purified the RNA, it still continued to splice itself. And finally, we had to turn the hypothesis around and say, you know, this would be unprecedented, but perhaps there is no protein enzyme. Perhaps the RNA by itself is catalyzing its own splicing reaction. And we were able to demonstrate that, and it became the first example of this large category of enzymatic RNAs. We dubbed the word ribozyne to name these, ribo for ribonucleic. acid enzyme for enzymatic activity.

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deprioritization during times of high network usage. We talk about all the different functions that RNA has and all the different types of RNA, which I didn't know. I'm just a simple experimental cosmologist, so learning about all the different types from Messenger to the structural component, the T RNA, obviously M, Messenger RNA has become part of the, I think it was Miriam's word of the year a couple of years ago. But DNA doesn't have such kind of prolific and multifiluous spinoffs to it. So why is it that DNA, is it possible to say that RNA is perhaps more important, more central?

We hear about RNA world, but we don't hear about DNA world. I want to get into that. But tell me, is it, is DNA sort of a one-trick pony? I mean, it's an important trick, but could you imagine, you know, if you can imagine a world of RNA first as a, a information-bearing molecule and then self-replication and all the other functions you mentioned. What do we need DNA for? Not everything needs DNA. So RNA can be a storage form of information just like DNA.

And to give you just a few examples, the influenza virus, the Ebola virus, and SARS-CoV-2 all have a genome made of RNA. They don't mess with DNA at all. They just use the RNA to encode the proteins that they need for their insidious infection of our bodies. DNA was presumably invented, so to speak, during evolution when the number of genes in an organism got to be very large, and DNA being much more stable than RNA by perhaps a thousandfold gave a real advantage. So DNA is a fantastic storehouse of genetic information. But you're right, Brian, it's a one-trick pony.

That's all it does. It does it very well. And we need it once we get to a size of a human genome to store our information. But then it's the RNA copied from that DNA that has this wonderful variety and complexity of activities. And we can talk about messenger RNAs and non-Messinger RNAs as sort of the two main categories. Absolutely. Yeah. And before we get there, I wanted to just mention, you know, this interplay with one of my heroes, George Gamow, who eventually ended up his career. He spent most of his career on the East Coast, but then ended up in Boulder right where you are, and you've

been there for quite a while. Did you ever meet him? I think he died relatively before you, your time there, right? I did not ever meet him. We did not overlap, but his daughter-in-law, Elfrida Gamoff, still runs a fabric shop in Boulder, and she gave me as a gift during a public ceremony, sort of, a small ceremony, George Gamoff's original tie from the RNA Tie Club, and that was, I almost cried because this was something that's in my book. This is something that is a really fun story about the RNA research in the early days. Tell us about the necktide club because it's so, it's such a great story. So after Watson and Crick determined the double helical structure of the DNA with Rosal and Franklin's help,

George Gamoff, who was a physicist of Big Bang fame, got very excited and wrote to them a rather whimsical letter and said, you know, you finally put biology on a firm scientific basis. And they thought he was a little wacky, and he was a little wacky, but they knew that he had a great reputation as a physicist, so they engaged in conversation with him, and he proposed that they figure out the genetic code from first principles, physics and decoding, cryptography. Now, what do I mean by the code? Because this is an important word. So the purpose of the coding parts of DNA, the information that it stores, is to instruct the body how to make particular proteins. Proteins are the movers and shakers in our body. They digest the food that's in our

stomach. They make our muscles move. They make our heartbeat. And they orchestrate the signals that carry information in our brains through the neurons. So proteins are, are the sort of endgame of life at the molecular level, and DNA is providing the instructions to make it. The DNA can't do this by itself. It copies itself into a messenger RNA, which then is what is fed through a machine called the ribosome to actually construct the protein molecules. So there has to be some kind of a code that translates between the A's T's, G, and C's of DNA and the 20 amino acids like lysine, phenylalanine, methyanine that are present in proteins. And if you think about the Rosetta Stone, which in a beautiful way had Greek hieroglyphics

and the translation, I'm sorry, it's not Greek, Egyptian, wrong place. hyroglyphics and their translation into Greek on the same stone. That was the key to figuring out translating the hieroglyphics. But we didn't have a rosetta stone for the DNA making protein, so scientists had to figure out what the code was. And Gamoff wanted to be part of this game. So he engaged Watson and Crick and a total of 20 scientists to form this RNA tie club. And each one was given a tie, which was manufactured in Pasadena, California. Watson bought the 20 ties, and George Gamoff bought tie clasps, one for had them made in New York City, one for each of the amino acids. And this was supposedly a way to stimulate these 20 eggheads

to figure out the code based on first principles. One of the eggheads that was around during Gamov's time was based here, eventually Harold Uri. And he, along with his student, Stanley Miller, made a famous experiment, which is now fallen into some, I wouldn't say discredit or discredit. dispute, but the applicability of the findings and the preparation of the Miller-Uri experiment are not representative, or at least it's not thought to be representative, of the early earth. Is there sort of an analog for, you know, this would be production of amino acids and this slurry that was electrocuted and then had some atmospheric components that at that time

in the 60s were thought to be representative, no longer are. Are there kind of an RNA version of this, or a precursor version? you could envision for, you know, a modern-day Miller-Uri experiment, check Keating experiment? Is there some way that we could sort of test via and perhaps falsify what would be needed as a minimal viable product to get evolution going if it was based on an RNA superstructure? Yes, yes, absolutely. And you said that very well, Brian, that what we can do in the laboratory is to at least

determine the feasibility of a particular. reaction mechanism to make the building blocks of RNA. One of the leaders in this field who really stimulated a lot of the research was Leslie Orgel, who was at the Salk Institute and who I knew very well on trips to La Jolla in the 1980s. We had many conversations about that, about this topic. I would say that right now, one of the stellar leaders in the prebiotic chemistry of RNA is John Sutherland, who is in England. And he has been able to make the building blocks of RNA from, you know, as you said, from a milleriori type of, in a very general sense, right? that you mix together small molecules that plausibly could have been found in the atmosphere of the early Earth, and then you add some kind of energy to the system. It could be an electrical

spark, which would be akin to lightning. It could be ultraviolet light, which is another form of energy that is readily available on the planet, and then see whether it's plausible that the building blocks of RNA could form. And they can be formed, and they can assemble into nucleotides. And then as Leslie Orgel showed, those nucleotides can string themselves together into strings of RNA, short scraps of RNA. And so we're beginning to see that the idea that RNA could have arose spontaneously on the primitive earth is a plausible conclusion to come to. One of Gamow's chief rivals was, of course, Fred Hoyle, who was the coiner of the term, the Big Bang, and as a pejorative, I've asked this, I actually said this when I gave a talk

at the Royal Institution last summer, that I thought it was a pejorative, meaning some sort of intimate act between couples, but they disabused me of that. notion. But at any rate, Tom, you know, one of Hoyle's other kind of hobby horses that he rode on quite frequently was panspermia, which another thing that sounds dirty, but it's not, is there sort of a fecundity metric or something that you could say if some genetic material came on an asteroid or a meteorite, which I'll give you when you come to La Jolla, I have a collection of these. But these meteorites sort of landing on Earth and then seeding Earth with the genetic material. If you were God, would you choose RNA to be encapsulated or riding on this

thing, or would you choose DNA? Definitely RNA, because although it has the disadvantage of being more short-lived, once it's freed from the constraints of that double helix, it can fold up into a myriad of shapes, each of which can have a very distinct and exciting biological activity. And by the this transpermia idea, you know, it's possible that that's the way that life started on Earth, that it came, you know, from some other, from some other planet, from some other asteroid or whatever. But, you know, that really doesn't, that's not a satisfying conclusion because then it just pushes the whole question back. How did life get started on Mars then, right? So it's not really much of a, much of an answer for a scientist. That's right.

It just pushes the question back onto some other field of science. It's true. It's one of the major kind of big bangs or alchemical type things that occur, right? The origin of a universe from a non-universe, the origin of life from non-living matter, the origin of consciousness from living matter that's not conscious. These are huge things. And I guess that brings up my next question to you is the eternal one. You know, if we need proteins to make structures and we need DNA,

to make proteins, then this eternal question of the, you know, chicken or egg type questions, they always arise. And by the way, Tom, you may not know this, but I found out how to solve the final question that everyone's so interested in. How can you actually know which came first, the chicken or the egg? I have solved that question. I'm waiting for the answer, Brian. Give me a hint.

This was given to me by one of my kids, one of my precocious young youngsters. He said, Dad, just go to Amazon. order a chicken, which you can do, and order an egg, and see which comes first. But in all seriousness, when you have the need to construct organelles or structures that make copies of themselves, how can we solve this, you know, solipsistic infinite regress? What do you think, if anything, can you say which came first? That was the conundrum for many years. if you need an informational molecule to pass down to the next generation, but the informational

molecule, DNA, can't do anything by itself. It needs protein enzymes to duplicate it. Then what are the odds that through a random chemical processes, both an informational molecule, a DNA, and a protein enzyme to copy it, would be formed in the same droplet of water at the same time. time seems like a stretch. That's why after catalytic RNA was discovered, the ribosine, everyone in that field became enormously excited because now if RNA is both an informational molecule and can assemble building blocks to make new RNA molecules, which is one of its activities as a ribosine, it's plausible that at the beginning there was RNA only. replicating itself, and then the proteins came along later, and then much later, DNA came along

as the more stable and permanent storehouse of information. Those swapping roles for a second where I'll become critical of RNA, moving to the opposite spectrum, where we find telomerase, which, as I understand it, is a type of DNA polymerase that is dependent on a structure or a template of RNA. Is it true that if that weren't the case or if there were some modifications, we could prevent, not explain birth of life, but prevent death of life? I mean, which is more interesting. So explain RNA's role in the end of life and in the degradation of cellular processes.

Yeah, well, so can we go, can we do the telomerase story? Yeah, please. I think we could flesh that one out a little bit. Yeah, please. It has been called the immortality enzyme, which sounds incredibly powerful, but you have to realize that it is immortality at the single cell level, not at the human being level. But it does, what occurs at the ends of our chromosomes is a limiting factor for the lifespan of the cells in our body.

And the exception to this is, well, okay, so how does this work? So there's specialized DNA, a little short sequence, TTA, GGG, repeated a thousand times at the ends of every one of our chromosomes, and that is unable to be copied or replicated by the enzymes that replicate the vast middle stretches of our chromosomes. Because of this failure to completely replicate the chromosome all the way out to the end, our chromosomes shrink every time the cell divides, and someone is keeping track of that inside the cell. It's another machine keeping track of that.

And when the end of the chromosome gets critically short, the cell is signaled to stop dividing. And so this gives most of our cells mortality. They undergo senescence. Now, we think this is a good thing because once you're an adult, you really don't want all of the cells in your body to continue doubling, right?

You would become exceedingly large. So this is a helpful thing. and there are some kind of cells, though, that have to escape this process, that have to be immortal. And these are our stem cells which rejuvenate our bodily tissues that wear out, and also our sex cells, our germline cells, that will give rise to the next generation. So how do they get immortality? Well, they have this little machine called Toulon. just meaning something that works on the telomere.

And it consists of a protein, which we discovered in my lab in Boulder called Tert, and an RNA discovered by Blackburn and Grider, who got the Nobel Prize also for the discovery of telomerase. And they found that this RNA, Blackburn and Grider found that this RNA was responsible for templating or direct. the building out of the ends of the chromosomes in, for example, stem cells and germline cells. And also in all the cells of our body early in embryogenesis before we're born, when all the cells still have to keep dividing.

So this immortality enzyme, how can you prove this is an immortality enzyme? Well, if you take a human skin cell, for example, or an epithelial cell, a retinal cell, that is not dividing and add this telomerase to it, it will grow, it will divide without bounds. It will become immortal. And this is now commonly used in the biotechnology industry to immortalize cells for growing up for medical purposes. Hey there, sorry for the interruption, but I have to ask you to help the life of this podcast and YouTube channel by subscribing no matter where you are.

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And how do you deliver this? Because, you know, I searched again going back to Amazon.com, where you can buy the catalyst as of today when this interview airs. I go to Amazon.com. I looked up, I found a Czech brand telomere lengthener supplement, which is, no, I do. It's not correct, man. No, I'm just teasing. There are an infinite number of these things.

I think you could monetize your success, but I know you're too ethical to do that. But these things are orally delivered, but you make the case in the book that probably the most effective way and diseases to treat and so forth would be in the blood. and you point out sickle cell disease has been one of the first to be treated in this way. I just find it miraculous as a physicist that you could take, you know, ingest something, and then it would propagate to almost every cell in the body. And it made sense for the first time, and I'm grateful to your explanation, the lucidity of it, that the blood is obviously an easy way to deliver stuff to the blood.

But what about other thing? I mean, if you were to really try to make a fountain of youth, I mean, how could you deliver it to bone cell, you know, a retinal cell, a toenail cell. I mean, wouldn't you have to do that in equal amounts, in equal proportions in just the right way? Is that a fool's errand? Yeah, it's extremely challenging. And for medical purposes, as you pointed out, and as I point out in my book, the human blood supply is really the most readily available organ, right? You can pump blood out of a person, temporarily, you can treat it in the laboratory, introduce new genes into it, and then return it to the person, and that is very difficult to do with cells in the middle of our brain as an extreme

example. Other tissues, when you inject nucleic acids into the bloodstream, they do readily find their way to the liver, for example. And so treating liver diseases is easy with nucleic acid therapies, such as RNA therapies, is easier than treating the heart as another example. So in an adult organism, certainly the availability of different tissues for medical treatment is is widely variable. And pivoting towards, you know, sort of the present of RNA and how it's impacted literally, you know, every human on earth almost, talk about CRISPR. Let's talk about CRISPR cast nine and its revolutionary transformative potential and already

has had great effect and impact. And I understand Jennifer Doudna, Doudna, who I'm hoping to get on the show, at some point that she worked with you, was it as an hope? undergraduate or? Yeah, she was a postdoctoral fellow. After she got her PhD in Harvard, she came to my lab for a few years and then started her own independent position at Yale University. So CRISPR is not divorced entirely from your research, obviously. So talk about CRISPR and where you see it as sort of its present impact, not just in terms of vaccinations and so forth. I didn't know until I read your book that had the word palindrome in it, which is pretty cool.

They should have made the word actually a palindrome. That would have been nice. But what is it? Explain it to a layperson, a simple, humble, experimental cosmologist, and what you as an expert feel is its potential transformative powers. Let me break it down into just talking a little bit about the origins of CRISPR, how it was discovered before I talk about the medical applications. because it's one of many examples of how medical advances come,

the most transformative ones tend to come not from studying patients in the clinic, but from studying some weird organism that exaggerates a particular or gives us a foothold into a particular phenomenon. In the case of CRISPR, it came from bacteria, and the bacteria were storing little snippets of DNA from viruses that it infected their family in the past. It was like they had a rolodex of bad actors, and as if to say, you know, if you ever see this guy come in, it's a bad thing. Try to eliminate it, okay? And so they had developed this CRISPR machinery for cutting up invading viruses based on having kept track of previous infections.

So why could this have any kind of a medical application? Well, when Jennifer Dowdena and Emmanuel Charpentier figured out the role of RNA in the CRISPR machine, this became clear how this was going to be a very valuable tool for biology and medicine. So the CRISPR consists of two parts. There's a protein part that acts as a little molecular scissors, makes a cut in the DNA, but how does it know where to cut? And this is where the RNA is so critical. The RNA acts as a guide and 20 units ASG season use in the RNA,

are looking for a match in the DNA. It's as if they, you know, the human genome, if it was a word document, would be about a million pages long. So, CRISPR can find not only the sentence within those million pages that matches its guide RNA, but it can also find even a single letter, and then it cuts at that point. Now, why is cutting DNA sounds dangerous, right?

Why is that useful? Well, because can then direct the repair of that DNA, because all living organisms have machinery within them that repairs broken DNA. It's so important to not have broken DNA that this has been developed billions of years ago. So they repair the DNA, and it's in that repair process that you can, for example, take a mutation in sickle cell. disease, or in cystic fibrosis, or in muscular dystrophy, or in one of 3,000 more rare genetic diseases, and at least in the laboratory, under controlled conditions, you can fix it using CRISPR. Medically, of course, it has to be safe as well as efficacious, and so things proceed more slowly than in our labs where we've been using this for almost a decade in my lab already and in

thousands of other labs around the world. But last year, just a few months ago, in December, the FDA Food and Drug Administration approved the first CRISPR therapy for sickle cell disease, which is a terrible affliction for many in the African American community. And I think many more applications will be forthcoming. As we... You said this place was steps from the water. We just haven't found the steps yet. How much did we save?

Enough. Enough to get lost! Or you could book a stay with Hilton. Welcome to your ocean front room. Just steps from the water. The Hilton sale is on now. Book on Hilton.com or the Hilton app and save up to 20% to get the stay you expected. When you want savings, not surprises.

It matters where you're. you stay. Hilton for the stay. He sort of wrap up some of the prepared questions I have will eventually segue to a couple of audience questions before we wrap up in a few minutes. So at the end of the book you have a

beautiful passage that cosmologists are intensely focused on understanding the nature of dark matter and dark energy. And I thought it was you might not be aware. There's actually a proposal to use RNA as a dark matter detector by my friends Katie Freeze and David Spurgo.

I'll send you a link to it. It's a fascinating, fascinating little paper. But you start talking about how these dark forces seem to be influencing the future of the universe, which is absolutely correct. So don't horn in into my field just yet. Let us other people into it. But it made me think. In our field of cosmology, there are some that speculate that the periodic table is not all there is.

That there may be, in fact, a dark matter universe. There might be a dark matter periodic table. In other words, we have 116 elements in our periodic table. Why limit nature to say there's just one dark matter candidate? And so it gives full employment to my theoretical colleagues and friends. But it made me think, do we know for sure that it's just it? It's just RNA and DNA. Those are the only two informational molecules.

Is that hubristic on our part? Or is there some principle in physics we call a no-go theorem? Is there something that says, no, that's all. there is. It could only be RNA and DNA that carry the informational code necessary for life. I would be of the camp that it's not necessarily just DNA and RNA, and that there's a lot of what we call frozen accident in evolution, which is that if a biological system stumbles upon something that works, it is often carried out. and continues to change a bit, but it's sort of frozen into the system, because if you have a

very complex system and you change one part of a complex machine, then you'd have to change all the other parts in order for it to be compatible. And so that's why we would be so excited to find life on another planet or on Europa, a moon of Jupiter, or whatever, because we'd be so excited to see if it really did use DNA and RNA, or it had a different, perhaps a different kind of nucleic acid as an informational molecule. And that would be different than, say, you know, junk DNA, which my former guest, Craig Venter, Craig, in his characteristic way, told me the only such thing as junk DNA is what's in his colleague's heads. He's quite irascible, as you probably know, very fascinating.

individual. But is there such a thing as junk RNA or is that just the name we give to stuff that we don't know if it has a function just yet? Right. So, and this is a, in my book, I actually call this the dark matter of the human genome. And about 75% of the DNA in all of our chromosomes does not encode for a protein. I said before, the purpose of DNA was to encode for proteins to specify and direct the formation of proteins, and that's really important. But three quarters of it is not doing that. But if you look at whether it's copied into RNA, this other 75%, you find that some of it is copied into RNA in the brain,

and different parts are copied into RNA in the liver and other parts in the skin or in the heart. And so, wow, that makes it seem like it might be valuable if it's being, only expressed in certain tissues. So there's a other people say, oh, it's just junk. It's just noise. Nature's not perfect. It's copying the DNA into RNA and it probably is just then gets degraded and doesn't do any harm. And therefore there's no reason for our body to worry about this dark matter. Well, I admit that some of this could be just junk or noise and not having a function, but I think it's premature to proclaim the death of being interested in that dark matter. And I think it's going to form the research topics for our students who are graduating now for many decades to come. Excellent.

And so as we sort of come to an end, I have a set of short answer questions, rapid fire questions, they call it in the podcast realm. But I guess before I do that, I'd love to get your impression on our career and what you and I do, and it gives us joy and meaning. But it's relatively unchanged as the professorship has not changed since the year 1080 when the University of Bologna was established in northern Italy. And I'm kind of curious. What do you see as the future of education, of, you know, pedagogy and the professorship in particular as it's applied to people like you and me today? Well, we're trying to change it, Brian. And there's a lot of resistance to it. But in our BioFrontiers Institute, we are breaking down the walls between the silo disciplines.

And we are providing a home for computational. scientists, mathematicians, physicists, biologists of many different brands, and engineers, also of many different subtypes, to work together on problems because we think it's more exciting to be problem-oriented and question-oriented than it is to stick to the traditional disciplines. and we have an interdisciplinary quantitative biology graduate program, which is teaching our PhD students, just a handful of them currently, but a very special handful in this same interdisciplinary manner. So I agree that most of academia has not changed in centuries, but I think a number of universities are forming institutes and other centers to try to accelerate discovery by combining the traditional

disciplines in new ways. Do you see AI or some sort of remote virtual reality having a role where, you know, my students could talk to Carl Sagan or Albert Einstein or talk to you, you know, rather than waste their time with me, do you see their, you know, kind of virtual presence or enabled by LLMs, particularly, as a possibility to augment our pedagogical frameworks for future students? I hope not. I find it a bit frightening. I find the, but it's coming, and it's going to transform our world, and I'm sure there will be, as you just indicated, some positive features of this, as well as a lot of invasion of privacy and distortion of truth and distortion of reality,

which I think we're just starting to realize that we need to come to grips with because it's going to happen and a lot of it is, you know, is dangerous. You know, go Scarlett Johansson, right? All right, Samantha. Sticking last question about academia before we wrap up with a couple of final finishing of questions. You're talking to a graduate student, a young graduate student starting her career, you know, could be the next Jennifer Doudna or whoever. But what do you advise them, not in scientific terms, but inevitably they're going to face setbacks. I always tell my students, if you don't have a crisis, you know, of confidence,

a quarter life crisis in graduate school, you're not doing it right. What would you say to a young graduate student to give them the advice to go into the impossible, that's the name of my podcast, it's sort of as advice to get through the inevitable setbacks, detours, competition, cutthroat as it may be, how would you advise a young student, not in academia, not the academic advice, but in sort of the life advice that you might give to a young person? Passion. So you need to have passion for what you're doing. if you have it, you will be able to overcome these setbacks and wrong turns. If you don't have it, find something else to do where you do have passion for it. Be an artist, be a musician.

Don't be a scientist just to have the three letters, PhD, after your name. Okay, next, Nobel Prize. If you could have won the Nobel Prize for any other scientific discovery, not the one you did, what would it be and why? I'm guessing cosmology, maybe. Oh, definitely literature. Because that's why I wrote the catalog. Yeah, that's this book.

That would be great. You need that. You need that ancomium for your career progression. Okay, literature. Excellent. Next question as we start to wrap up. So there's a famous quote from Feynman where he asked the following. He said, you know, if you were asked in some cataclysm, what sentence contains the most information in the fewest words about the natural world that science has led us to know about.

and he said the atomic hypothesis that everything is made of little atoms whirling around and doing their little gyrations and so forth. I like to pivot it around in the words of Arthur C. Clark, who's the namesake of the center that I am co-associate director of here at UCSD, he said that any sufficiently advanced technology is indistinguishable from magic. Now, I want you, Tom, to imagine that we're sending out, you know, a billboard into space and we're saying, this is the greatest thing that humans have ever done, ever invented, or ever discover. about the natural world? What would it be? And it could be in exactly your research if that's what moves you. Well, I think showing the chemical structure of a piece of RNA would be something that probably could be deciphered by intelligent beings who otherwise would have difficulty communicating with us. And, you know, who knows whether RNA is universal in the universe, But I'd give it a shot.

The last question comes from Sir Arthur C. Clark, who said, among many things, for every expert, there's an equal and opposite expert. But he also said the following. He said, when an elderly and distinguished scientist says something is possible, he or she is most likely right. But when he or she says something is impossible, they're very most likely wrong. What have you been wrong about, if anything, Tom? Oh, you could just ask anyone in my laboratory that I am wrong about 50% of the time. And I think that, and I hope that they enjoy doing the experiment that I suggest. They don't always do it, but sometimes they do the experiment that I suggest, and they come back to me,

and they don't say, you're wrong, because they're very respectful. But they say, well, it didn't work out as you thought it would. And, but then we move forward, right? The important thing in science is not to be right all the time, but to have an idea that is testable, and then you test it, and then it's either right or wrong, and that allows you to make progress often more slowly than we wished, but progress nonetheless. Phenomenal. Thomas Check is an American chemist who shared the 1989 Nobel Prize in Chemistry with Sidney Altman for their discovery, the catalytic properties of RNA, and is the author of this phenomenal book. I actually made it into an audio book using some fancy AI software

because the audiobooks sound out, but you should read it. You should read the audio version of it. Tom, I'm advising you, and you don't pay for this advice, so take it what it's worth. But it's a lovely book. It's full of stories. It's beautifully written. And I think, you know, Stockholm may be calling again for the Literature Prize not too long from now. Brian, it's been a pleasure talking to you. This has been great. I hope to see you when you come to Aloha. Bye, Tom. Yamava Resort and Casino at San Manuel is California's number one entertainment destination for today's superstars. Catch the Jonas Brothers return to the Yamava Theater stage on April 30th,

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