Podcast appearances and mentions of carol greider

“By the time we finished walking across this great lawn, we had decided on this exciting experiment.” —Elizabeth Blackburn on meeting her collaborator, Jack Szostak at a research conference. Elizabeth Blackburn, Carol Greider, and Jack Szostak won the 2006 Lasker Award for the prediction and discovery of telomerase, the enzyme that maintains the ends of chromosomes (telomeres). Blackburn and Szostak predicted the existence of such an enzyme, based on experiments they did in yeast and tetrahymena. Blackburn and Greider showed that this enzyme, telomerase, really does exist. The research of these three scientists broke open a new field and forever changed science and medicine.  

Does life exist beyond Earth, or is our planet genuinely unique? Can we recreate the origins of life in a lab? And what role does Mars play in the quest for cosmic life? I had the extraordinary honor of discussing this with two outstanding scientists, Mario Livio and Jack Szostak. Mario and Jack just released their new book, Is Earth Exceptional?, which seeks to answer whether life is a freak accident or a chemical inevitability. Tune in and join us for this mesmerizing exploration! Mario Livio is an astrophysicist and author known for his work in cosmology and his popular science books. Livio has significantly contributed to our understanding of dark energy, black holes, and other cosmic phenomena.  Jack Szostak is a prominent biologist and Nobel Laureate known for his significant contributions to understanding life's fundamental processes. He was awarded the Nobel Prize in Physiology or Medicine in 2009, along with Elizabeth Blackburn and Carol Greider, for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase. Key Takeaways: 00:00:00 Intro 00:01:33 “Life existing only on Earth is arrogant.” 00:04:09 Miller–Urey experiment 00:08:35 Does extraordinary evidence exist? 00:10:12 Judging a book by its cover 00:14:11 The origin of life  00:22:18 Thoughts on Rare Earth by Ward and Brownlee 00:24:59 The role of magnetite in the origin of life  00:31:30 Life on Mars?  00:55:15 Drake equation  00:58:54 Outro  Additional resources: ➡️ Learn more about Mario Livio:

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Der 11. Februar ist der "Internationale Tag der Frauen und Mädchen in der Wissenschaft". Zu diesem Anlass wollen wir euch in einem Sonderformat Frauen vorstellen, die in der Genetik einen wichtigen Beitrag geleistet haben. Im ersten Teil dieser Doppelfolge stellen wir euch vier Forscherinnen vor: Barbara McClintock, Elizabeth Blackburn, Carol Greider und Susan Lindquist.

Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start? Dr. Greg Hundley: Very good. Dr. Carolyn Lam: Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG. Dr. Greg Hundley: Ah, Carolyn. So what did they find in this subgroup of patients? Dr. Carolyn Lam: So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery. Dr. Greg Hundley: Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go. Dr. Greg Hundley: All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery. Dr. Greg Hundley: So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection. Dr. Carolyn Lam: Wow, fascinating. So what did today's paper find? Dr. Greg Hundley: Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper? Dr. Carolyn Lam: Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right? Dr. Greg Hundley: Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn. Dr. Carolyn Lam: Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs. Dr. Carolyn Lam: The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation. Dr. Carolyn Lam: But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit. Dr. Greg Hundley: Okay. Carolyn, what a beautiful summary here. So what's the take home message here? Dr. Carolyn Lam: So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases. Dr. Carolyn Lam: Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention. Dr. Greg Hundley: Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study? Dr. Carolyn Lam: Let's go, Greg. Dr. Mercedes Carnethon: Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization. Dr. Mercedes Carnethon: And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you. Professor Gregory Lip: Hello there. Dr. Connie Hess: Thank you for having me. Dr. Mercedes Carnethon: Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study? Dr. Connie Hess: Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about. Dr. Connie Hess: And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI. Dr. Connie Hess: And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. Dr. Connie Hess: And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out. Dr. Connie Hess: And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction. Dr. Connie Hess: Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication. Dr. Mercedes Carnethon: All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind? Professor Gregory Lip: Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes. Professor Gregory Lip: So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding. Professor Gregory Lip: We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well. Dr. Mercedes Carnethon: Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study? Dr. Connie Hess: Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt. Dr. Connie Hess: I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic. Dr. Connie Hess: A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it. Dr. Connie Hess: I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy. Dr. Mercedes Carnethon: I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal. Dr. Mercedes Carnethon: This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Hace un siglo, la esperanza media de vida era de 50 años, al menos en los países desarrollados. Hoy, podemos esperar vivir casi 80 años. Con un mayor conocimiento de lo que nos mantiene sanos, nuestra esperanza de vida ha aumentado espectacularmente. El enigma de la inmortalidad celular determina nuestras vidas: desde lo bien que envejecemos, hasta cuánto tiempo viviremos. Las empresas que crionizan cuerpos o partes del cuerpo con fines médicos están creciendo. Actualmente se puede congelar las válvulas del corazón con el fin de hacer un trasplante, ¿se podrá congelar todo el corazón, el hígado o los riñones? La criopreservación es vista como la esperanza de vida eterna, o al menos en la esperanza de una cura donde antes no parecía posible la curación. Es un sueño de la humanidad poder ser congelados después de la muerte con el fin de ser descongelados en algún momento del futuro y volver a la vida. La criopreservación o congelación es la gran esperanza investigada por los científicos. En esencia, no es más que la congelación y el almacenamiento de células humanas en nitrógeno líquido, pero resulta un procedimiento técnico difícil. Cualquier hombre o mujer puede elegir ser almacenado en nitrógeno líquido cuando está clínicamente muerto, y ser conservado así hasta que le llegue el momento de devolverle a la vida. Proliferan los institutos criogénicos y algunos almacenan los cuerpos de familias enteras e incluso de sus mascotas. Pero, ¿cuál es la esperanza real para aquellas personas que se han congelado criogénicamente cuando han muerto? Las empresas que crionizan cuerpos o partes del cuerpo con fines médicos están creciendo. En medicina la ciencia del frío se empieza a usar a menudo. Actualmente ya se puede congelar las válvulas del corazón con el fin de hacer un trasplante, la sangre de los propios pacientes para posibles trasfusiones, y también la del cordón umbilical de los recién nacidos. Incluso en los centros de fertilidad, la posibilidad de congelar óvulos se ha convertido en un negocio. La ciencia ha descubierto la que podría ser la clave de la eterna juventud, el elixir de la vida. A medida que nuestras células se dividen y crecen, un telómero (un tapón de ADN pequeño que hay al final de cada cromosoma) protege nuestro ADN de los daños. Los científicos comprobaron que algo agregaba nuevo ADN en los extremos de los cromosomas. Los telómeros no se desgastaban, de forma que las células podían duplicarse infinitamente. Eran, de hecho, inmortales. Habían encontrado una enzima, un catalizador químico que mantenía la longitud de los telómeros y hacía que las células se reprodujeran sin límite. La llamaron la telomerasa. Esta enzima mantiene el ADN joven y permite que las células puedan duplicarse infinitamente. La mala noticia es que puede matar al activar también las células cancerígenas. En 2009, el descubrimiento del mecanismo que mantiene jóvenes nuestras células y activa el cáncer recibió el premio Nobel de Medicina. Las profesoras Elizabeth Blackburn, Carol Greider, y Jack Szostack compartieron el premio. Fue el reconocimiento a un viaje que había comenzado hacía 30 años. Este descubrimiento, junto con otros hallazgos sobre el envejecimiento celular y su rejuvenecimiento, están preparados para mejorar radicalmente la forma en la que envejecemos. Varios medicamentos nuevos basados en la telomerasa han entrado en la fase II y III de ensayos clínicos. Cuando se encuentre un medicamento que active la telomerasa no sólo curará el envejecimiento, también ayudará a curar todas las enfermedades que conocemos.

I take a break from the Coronavirus to talk about what I think is the biggest story of 2020 that went unnoticed by the mainstream media... the allegation that Nobel Laureate Dr. Carol Greider stole work from Dr. Bret Weinstein. Important links: Evergreen State College Documentary (Part 1 of 3): https://youtu.be/FH2WeWgcSMk Bret Weinstein on "The Portal": https://youtu.be/JLb5hZLw44s YouTube: https://youtu.be/BsON9mQc68Y Patreon: patreon.com/zachsacher --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/rule8politics/support

This podcast discusses the results and implications of a recent study on gender bias in speaker introductions at an international oncology conference. This JCO Podcast provides observations and commentary on the JCO article "Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference" by Duma et al. My name is Dr. Tatiana Prowell. I am an Associate Professor of Oncology at Johns Hopkins Kimmel Cancer Center and Breast Cancer Scientific Liaison at the U.S. Food and Drug Administration in Silver Spring, Maryland. My oncologic specialty is breast cancer. In the article that accompanies this podcast, Duma and colleagues report the results of a retrospective observational study of speaker introductions at two consecutive years of ASCO Annual Meetings. The investigators hypothesized that female speakers in oral sessions would be introduced with a professional form of address less frequently than male speakers. For the purposes of the study, they defined a professional address as use of a title such as Professor or Doctor, followed by the speaker’s full name or last name, or the speaker’s full name followed by doctoral degree. A team of four male and four female reviewers analyzed 781 video recordings of oral sessions from the 2017 and 2018 ASCO Annual Meetings and recorded the gender of the introducer and speaker and how the speaker was introduced. They found that female speakers received a professional form of address 62% of the time whereas male speakers were introduced professionally 81% of the time, a difference that was statistically significant. Duma and her colleagues also assessed whether the gender of the introducer was associated with a difference in the likelihood of receiving a professional introduction. They found that male moderators introduced female speakers professionally a little more than half the time, whereas they introduced men professionally in 80% of cases.  Interestingly, when serving as introducers, women were more likely than men to include a professional form of address, which they did about three-quarters of the time, regardless of whether they were introducing men or women.  Perhaps the most striking result of the study was that one in six female speakers was introduced by her first name only, a surprising degree of informality for a high-profile conference like the ASCO Annual Meeting, which draws more than 40,000 attendees per year. By comparison, male speakers were introduced by first name alone in just 3% of presentations. In a multivariate analysis that included gender, degree, academic rank and geographic location of the speaker’s institution, male speakers were 2.5 times more likely to receive a professional introduction compared to female speakers.    This study adds to a growing body of literature in medicine investigating the prevalence of gender bias in speaker introductions. For example, previous studies of speaker introductions over a 3 year period of Mayo Clinic Internal Medicine Grand Rounds and at an American Society of Colon and Rectal Surgeons Annual Meeting reported similar findings. In both cases, female speakers were less likely than men to be introduced using a professional form of address, and women introducers more consistently referred to speakers by a professional title, regardless of whether the speaker they were introducing happened to be a man or a woman.   This study raises two key questions: why do we see this, and how can we fix it? A speaker introduction, especially at an international conference, is by definition a formal ritual, and yet one so familiar to us that we may have lost sight of its purpose. It would be easy enough for speakers to introduce themselves. Every speaker has an opening slide that shows his or her name and institutional affiliation. So why choose someone, and often someone well-known within the field, whose role is to introduce the speakers at all?  What leads us to say, “Dr. Carol Greider is Bloomberg Distinguished Professor, Director of Molecular Biology and Genetics at Johns Hopkins University, and a recipient of the 2009 Nobel Prize in Medicine”? I believe we do this for two reasons. First, formal introductions provide a moment, however brief, to demonstrate our collective respect for the speaker and his or her scientific contributions. Second, the information in the introduction signals to any who are not familiar with the speaker that the person is credible, knowledgeable, and worthy of our attention. Although more than 50% of medical school matriculants and about 40% of medical school faculty are women, they remain underrepresented at higher academic ranks and in leadership roles. Only about one-quarter of full professors are women, and fewer than 1 in 5 department chairs are women. Women are also less likely than men to be the first or senior author of manuscripts and thus less likely to be standing at the podium. As a result, the names and work of women in medicine may well be less familiar to the audience. Female introducers may therefore be more likely to assign value to use of a professional form of address. If this were true, one might expect to see women more consistently use a professional form of address when introducing speakers, and this is in fact what Duma and her colleagues observed.    The more troubling question is why men approached the introduction of male and female speakers so differently and why male speakers were 2.5 times more likely to be introduced with a professional title than women. I believe that most moderators, if presented with data from their own sessions, would be surprised to learn that they introduce men and women differently. This is called unconscious bias, and we are all susceptible to it. While the root causes of unconscious gender bias are numerous, one of these is surely the dearth of women occupying senior positions in medicine. As a community, we have tremendous power to remedy this source of unconscious bias. But while we can all re-commit ourselves to mentoring and sponsoring women in order to create more visible examples of female leaders in medicine, these efforts will not change the face of medicine, nor eliminate our unconscious gender bias, overnight. And yet, this is a change that needs to be made now. A male colleague of mine described introducing a woman at the podium by her first name as the verbal equivalent of rubbing the shoulder of a female professional acquaintance, then extending a handshake to a male professional acquaintance, that is to say, an inappropriate degree of familiarity with the woman. However, even in circumstances where the introducer and speaker are well-known to one another, formal settings call for formality. I call my physician husband “honey” at home, but if I were moderating an ASCO Annual Meeting session in which he was a panelist and said “Honey, why don’t you take that question?” it would of course be ridiculous.  Using respectful forms of address in formal settings like conference sessions is ultimately a mark of professionalism and, in 2019, non-negotiable.    The good news is that, unlike many problems in medicine, this one has a couple of solutions that we can implement immediately. We can provide a simple standardized script at the podium that ensures all speakers receive an equitable introduction. All conferences should implement this now, and in fact, motivated by Duma and her colleagues’ work, session chairs will receive such a script for introductions at the 2020 ASCO Annual Meeting. Perhaps more importantly, though, we can appreciate the formal introduction as a ritual that has been conserved through generations of scientists for a reason. Regardless of our gender, all of us as physicians remember that feeling when were July interns and the attending said of us on rounds something like, “Dr. Smith will be back to explain the plan to you in more detail.” In that moment, when we were called Doctor before an audience of our patients and our peers, we felt respected, capable, confident, and proud. Let’s commit to ensuring that all of our colleagues have that feeling every time they take the podium.    This concludes this JCO Podcast. Thank you for  

Elissa Epel, today’s guest, is an expert in the field of telomeres. She co-wrote the The Telomere Effect with Dr. Elizabeth Blackburn, who won a Nobel Prize for discovering telomerase. Elissa, an associate professor at UCSF, explains in this conversation how certain behaviors and experiences can impact telomere length. She talks about stress, for example, which affects telomeres differently depending on the kind of stress. She also offers insight into how to protect yourself from premature cellular aging through mindset and lifestyle choices. Find Out More About Elissa Here: Elissa Epel at UCSF@Dr_Epel on TwitterElissa.Epel@ucsf.eduwww.telomereeffect.com In This Episode: [01:51] - Elissa speaks about why we should care about telomeres, and what we need to know about them. She reveals that much of our aging is about our lifestyle. [03:35] - Stephan recaps what telomeres are. Elissa then expands on what he has been saying and offers some insight into how short, worn-out telomeres lead to aging issues. Short telomeres can actually impact young people as well, she reveals. [05;40] - There’s a commercially available test you can take to find out the length of your telomeres (if that’s something you want to know). Elissa explains that in certain cases, people are unhappy to discover their results. [08:42] - How can we get tested? Elissa lists some testing companies (including Life Length, Telomere Diagnostics, and Repeat Diagnostics). She then offers advice on how often to test your telomere length. [10:15] - Elissa clarifies what she meant by a “residential retreat” a moment ago. She then discusses how valuable these can be. [14:29] - We hear about the effects of these residential retreats on telomere length and telomerase. [16:13] - In response to Stephan’s request for things for people who aren’t really into meditating can do instead, Elissa talks about tai chi and qigong. She also talks about the importance of being able to change your perspective and the way you’re thinking when facing stress. [19:52] - Stephan mentions Elissa’s book as it relates to stress. Elissa talks about different types of stress and their different impacts on telomere length. She then emphasizes the possibility of maintaining telomere length even if they’re currently shorter than you might like. [23:17] - Stephan and Elissa talk about positive addictions. Stephan recommends Way of Life, an iPhone app. [25:17] - Elissa talks more about forming habits and what she calls the “golden rules of behavior change.” She recommends asking yourself how confident you are that you’ll maintain your behavior, as the answer reveals a great deal about the likelihood that you’ll follow through. [28:01] - We learn that habits have three components: the cue, the habit itself, and the reward. To break a bad habit, you can change the cue. [29:52] - Where does sleep fit into the equation for Elissa? She reveals that shorter telomeres are associated with various sleep issues. [32:41] - Elissa discusses the weak relationship between BMI and shorter telomeres. [34:52] - Stephan and Elissa discuss abdominal fat. [35:52] - We learn that Elissa’s co-author, Dr. Elizabeth Blackburn, discovered telomerase with her student Carol Greider. Elissa then talks about the slow growth of science, specifically in its response to this discovery. [40:16] - We shift to the topic of nutrition and dieting. Elissa talks in particular about a study by Janet Tomiyama regarding caloric restriction, and reveals that nutrition is more important for telomere length. [44:12] - What would Elissa recommend for supplements when it comes to telomeres? [45:25] - Elissa talks about what a pregnant woman can do to give her baby the best shot at having long telomeres. [47:19] - Stephan brings up the topic of banking stem cells. Elissa explains that stem cells are the cells with the highest levels of telomerase. [49:08] - How can people find Elissa’s book? And does she have any other resources to recommend to listeners? [50:43] - Is there a strong correlation between your sense of purpose in life and the length of your telomeres? Elissa speaks to the perhaps surprisingly deep importance of feeling a sense of purpose. Links and Resources: Elissa Epel at UCSF@Dr_Epel on TwitterElissa.Epel@ucsf.eduwww.telomereeffect.comThe Telomere EffectDr. Elizabeth BlackburnTelomeraseUCSFTelomeresRhinovirusPeter DruckerLife LengthTelomere DiagnosticsRepeat DiagnosticsDeepak ChopraTai chiQigongMind & Body Tips (on The Telomere Effect)Way of LifeJerry SeinfeldGlucoseDr. Michael Breus on the Optimized GeekThe Power of When by Dr. Michael BreusSleep apnea Blue lightMelatonin Growth hormoneBMI AdiposeInsulin Intra-abdominal (or visceral) fatCytokinesEukaryotic organismsTetrahymenaAnemia FolateCaloric restrictionIntermittent fastingCarol GreiderJanet TomiyamaFree radicalsOxidative stressAntioxidants Insulin resistanceWorld Health OrganizationOmega-3 Fatty AcidsStem cellsBanking stem cellsDr. Harry Adelson on the Optimized Geek

Telomeres were first recognized in the late 1930s as important structures on chromosome ends. In the 1970s the sequence of these structures was identified in the ciliated protozoa Tetrahymena by Elizabeth Blackburn. In the 1980s telomerase was discovered as an enzyme that elongates telomeres and compensates for natural telomere shortening. Carol Greider, Director of Molecular Biology and Genetics, Johns Hopkins University, discusses the journey from these curiosity driven discoveries to the appreciation of the role of telomeres in human disease. Series: "UC Berkeley Graduate Lectures" [Science] [Show ID: 28053]

Telomeres were first recognized in the late 1930s as important structures on chromosome ends. In the 1970s the sequence of these structures was identified in the ciliated protozoa Tetrahymena by Elizabeth Blackburn. In the 1980s telomerase was discovered as an enzyme that elongates telomeres and compensates for natural telomere shortening. Carol Greider, Director of Molecular Biology and Genetics, Johns Hopkins University, discusses the journey from these curiosity driven discoveries to the appreciation of the role of telomeres in human disease. Series: "UC Berkeley Graduate Lectures" [Science] [Show ID: 28053]

Telomeres are the chromosomes end-part, that are needed to protect chromosome ends. Due to the way chromosomes are copied, these telomeres shorten with each round of cell division. This shortening is kept in check by the enzyme telomerase which elongates telomeres. However because of the limited amount of telomerase, telomere shorten with age in humans. People who cannot effectively elongate telomeres may show manifestations of a Telomere Syndrome, which include age-related diseases such as bone marrow failure, immune senescence and pulmonary fibrosis. Carol Greider, 2009 Nobel Laureate and professor at Johns Hopkins University, discusses how the seemingly benign structure on chromosome ends can underlie human disease. Series: "UC Berkeley Graduate Lectures" [Science] [Show ID: 28052]

Telomeres are the chromosomes end-part, that are needed to protect chromosome ends. Due to the way chromosomes are copied, these telomeres shorten with each round of cell division. This shortening is kept in check by the enzyme telomerase which elongates telomeres. However because of the limited amount of telomerase, telomere shorten with age in humans. People who cannot effectively elongate telomeres may show manifestations of a Telomere Syndrome, which include age-related diseases such as bone marrow failure, immune senescence and pulmonary fibrosis. Carol Greider, 2009 Nobel Laureate and professor at Johns Hopkins University, discusses how the seemingly benign structure on chromosome ends can underlie human disease. Series: "UC Berkeley Graduate Lectures" [Science] [Show ID: 28052]

Conversations host Harry Kreisler welcome Nobel Laureate Carol Greider, Daniel Nathans Professor and Director of Molecular Biology and Genetics, Johns Hopkins University, for a discussion of her intellectual odyssey. Topics covered include her education; her Nobel winning research on telomeres and telomerase; the implications of this research for treatment of disease; science education; and women in science. Series: "Conversations with History" [Science] [Show ID: 28054]

Conversations host Harry Kreisler welcome Nobel Laureate Carol Greider, Daniel Nathans Professor and Director of Molecular Biology and Genetics, Johns Hopkins University, for a discussion of her intellectual odyssey. Topics covered include her education; her Nobel winning research on telomeres and telomerase; the implications of this research for treatment of disease; science education; and women in science. Series: "Conversations with History" [Science] [Show ID: 28054]

Special Guest: Susan Raymond---Academy Award-winning filmmakers Alan and Susan Raymond are among America’s most distinguished documentary filmmakers. The Raymonds have produced a feature length documentary on education entitled JOURNEY INTO DYSLEXIA that profiles students and adults who struggled in school and then succeeded in life. This program addresses the public’s misunderstanding of learning disabilities and demonstrates the great potential of each dyslexic individual. Included are entrepreneurs, inventors, Artist Micro Sculptor Willard Wigan and Nobel Laureate Dr. Carol Greider. http://www.videoverite.tv/pages/filmsmain-2011.html Special Guest: Lee Grossman, Interim Executive Director of the International Dyslexia Association (IDA).  Grossman came to IDA from Advance Enterprises, a global consulting firm in Washington, D.C., where he served as President and CEO.  He also spent over 20 years at the Autism Society of America (ASA), where for over 10 years he served as Chair of the Board of Directors and later President and CEO.    www.interdys.org Special Guest: Larry B. Silver, MD; Dr. Silver is a Child and Adolescent Psychiatrist, recently retired from private practice.  He is Clinical Professor of Psychiatry at the Georgetown Medical Center in Washington, D.C.  Prior to his current activities, he was Acting Director and Deputy Director of the National Institute of Mental Health. In 1996, he received the American Academy of Child and Adolescent Psychiatry’s Lifetime Achievement Award for his contributions to the study and treatment of Learning Disabilities. www.LDAAmerica.org