RNA that facilitates the addition of amino acids to a new protein
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We love to hear from our listeners. Send us a message. On this week's episode, Michelle Werner, CEO at Alltrna, talks transfer RNA (tRNA) therapy with host Ben Comer and guest co-host Anna Rose Welch, editorial and community director at Advancing RNA. Werner explains why a single engineered tRNA therapy has the potential to treat "hundreds, if not thousands," of rare genetic diseases, and how her own child's rare disease diagnosis shaped her career and approach to drug development. Werner also discusses Alltrna's use of AI and machine learning for drug optimization, the company's planned use of basket trials, and more. This episode is brought to you by Avantor. For more information, visit avantorsciences.comAccess this and hundreds of episodes of the Business of Biotech videocast under the Business of Biotech tab at lifescienceleader.com. Subscribe to our monthly Business of Biotech newsletter. Get in touch with guest and topic suggestions: ben.comer@lifescienceleader.comFind Ben Comer on LinkedIn: https://www.linkedin.com/in/bencomer/
In this week's episode we'll learn more about how phosphoseryl-tRNA kinase inhibition promotes cell death in acute myeloid leukemia, or AML; APOE gene variants and their association with post-hematopoietic stem cell transplant outcomes in AML; and pathways by which chronic inflammation and oxidative stress may lead to cardiomyopathy in patients with sickle cell disease.Featured Articles:PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells Common Hereditary Variants of the APOE Gene and Posttransplant Outcome in Acute Myeloid Leukemia 17R-Resolvin D1 Protects Against Sickle Cell Related Inflammatory Cardiomyopathy in Humanized Mice
In this episode, we review the high-yield topic of tRNA from the Biochemistry section.Follow Medbullets on social media:Facebook: www.facebook.com/medbulletsInstagram: www.instagram.com/medbulletsofficialTwitter: www.twitter.com/medbullets
This week on The Genetics Podcast, Patrick is joined by Michelle Werner, CEO at Alltrna and CEO/Partner at Flagship Pioneering. They discuss Alltrna's promising findings from its first preclinical study on using tRNA to rescue stop codon disease, the strategic use of basket trials, and more!Show Notes: 0:00 Intro to The Genetics Podcast01:00 Welcome to Michelle02:13 Overview of Alltrna's aims and the advantages of using tRNA to tackle stop codon disease5:27 Using basket trials for genetic diseases08:03 Highlights from Alltrna's first preclinical study using tRNA to restore protein production to clinically meaningful levels in methylmalonic acidemia (MMA) and phenylketonuria (PKU)14:02 Considerations in delivery techniques and Alltrna's use of nanoparticles19:22 Stability of tRNA and how engineered tRNAs are recognized in vivo 23:12 Strategic design of basket trials and diseases that are covered26:16 Adaptive trial design in the rare genetic disease setting28:15 Michelle's experience with regulatory organizations on new approaches to trial design32:14 Insights from spearheading Alltrna and Flagship Pioneering's innovative approaches 37:26 Michelle's lessons from working in big pharma versus a small biotech start-up40:50 Closing remarks and a call for collaboratorsFind out more Alltrna (https://www.alltrna.com/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link
In this episode of the In Vivo podcast, Michelle Werner, CEO of Alltrna, discusses using tRNA as a therapeutic modality for rare diseases, including those stemming from nonsense mutations.
This week, we welcome Michelle Werner, CEO of Alltrna and CEO/Partner at Flagship Pioneering. Michelle and her team are working at the cutting-edge of tRNA therapies, which they hope will present a scalable treatment method for people in the rare and ultra-rare disease communities. Join Patrick and Michelle for an exciting conversation about this breakthrough technology, from the transferable potential of this new modality across stop codon diseases, to Michelle's personal passion for delivering workable solutions to the rare disease community.
Subscribe to our channel: https://www.youtube.com/@optispan Related episodes: Reversing Biological Age: Have we finally found the answer?: https://youtu.be/ivP3QTyQ2d4 Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing fascinating work in the longevity field. One of these was Mark McCormick, an Assistant Professor at the University of New Mexico (UNM) Department of Biochemistry and Molecular Biology. At UNM, Mark runs a lab that investigates age-delaying drug targets, develops machine learning tools for studying aging, and identifies conserved aging mechanisms and pathways in model organisms and humans. Mark previously completed a postdoc with Brian Kennedy at the Buck Institute for Research on Aging, a PhD in Biochemistry and Molecular Biology with Cynthia Kenyon at the University of California, San Francisco, and a B.S. in Mechanical Engineering as well as a B.S. in Biology from the University of Texas at Austin. In this episode, Matt and Mark chat about aminoacyl-tRNA synthetases, a group of enzymes that play an essential role in protein synthesis. They discuss the promise and risks of tRNA synthetase inhibitors to treat diseases of aging and extend life- and healthspan (spoiler: don't take tRNA synthetase inhibitors yet). They also talk about why Mark's lab has held off on doing mouse experiments thus far, the challenges of proving causality in longevity experiments, interventions about which Mark is optimistic (or not), and more. Producers: Tara Mei, Nicholas Arapis Video Editor: Jacob Keliikoa DISCLAIMER: The information provided on the Optispan podcast is intended solely for general educational purposes and is not meant to be, nor should it be construed as, personalized medical advice. No doctor-patient relationship is established by your use of this channel. The information and materials presented are for informational purposes only and are not a substitute for professional medical advice, diagnosis, or treatment. We strongly advise that you consult with a licensed healthcare professional for all matters concerning your health, especially before undertaking any changes based on content provided by this channel. The hosts and guests on this channel are not liable for any direct, indirect, or other damages or adverse effects that may arise from the application of the information discussed. Medical knowledge is constantly evolving; therefore, the information provided should be verified against current medical standards and practices. More places to find us: Twitter: https://twitter.com/optispanpodcast Twitter: https://twitter.com/optispan Twitter: https://twitter.com/mkaeberlein Linkedin: https://www.linkedin.com/company/optispan https://www.optispan.life/ Hi, I'm Matt Kaeberlein. I spent the first few decades of my career doing scientific research into the biology of aging, trying to understand the finer details of how humans age in order to facilitate translational interventions that promote healthspan and improve quality of life. Now I want to take some of that knowledge out of the lab and into the hands of people who can really use it. On this podcast I talk about all things aging and healthspan, from supplements and nutrition to the latest discoveries in longevity research. My goal is to lift the veil on the geroscience and longevity world and help you apply what we know to your own personal health trajectory. I care about quality science and will always be honest about what I don't know. I hope you'll find these episodes helpful!
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
In this episode of the Epigenetics Podcast, we talked with Upasna Sharma from UC Santa Cruz about her work a number of interesting projects on H2A.Z and telomeres, the impact of paternal diet on offspring metabolism, and the role of small RNAs in sperm. In this interview Upasna Sharma discusses her work on the study of the paternal diet's impact on offspring metabolism. She reveals the discovery of small non-coding RNAs, particularly tRNA fragments, in mature mammalian sperm that may carry epigenetic information to the next generation. She explains the specific alterations in tRNA fragment levels in response to a low-protein diet and the connections found between tRNA fragments and metabolic status. Dr. Sharma further explains the degradation and stabilization of tRNA fragments in cells and the processes involved in their regulation. She shares their observation of tRNA fragment abundance in epididymal sperm, despite the sperm being transcriptionally silent at that time. This leads to a discussion on the role of the epididymis in the reprogramming of small RNA profiles and the transportation of tRNA fragments through extracellular vesicles. The conversation then shifts towards the potential mechanism of how environmental information could be transmitted to sperm and the observed changes in small RNAs in response to a low-protein diet. Dr. Sharma discusses the manipulation of small RNAs in embryos and mouse embryonic stem cells, revealing their role in regulating specific sets of genes during early development. However, the exact mechanisms that link these early changes to metabolic phenotypes are still being explored. References Sharma, U., Conine, C. C., Shea, J. M., Boskovic, A., Derr, A. G., Bing, X. Y., Belleannee, C., Kucukural, A., Serra, R. W., Sun, F., Song, L., Carone, B. R., Ricci, E. P., Li, X. Z., Fauquier, L., Moore, M. J., Sullivan, R., Mello, C. C., Garber, M., & Rando, O. J. (2016). Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science (New York, N.Y.), 351(6271), 391–396. https://doi.org/10.1126/science.aad6780 Sharma, U., Sun, F., Conine, C. C., Reichholf, B., Kukreja, S., Herzog, V. A., Ameres, S. L., & Rando, O. J. (2018). Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm. Developmental cell, 46(4), 481–494.e6. https://doi.org/10.1016/j.devcel.2018.06.023 Rinaldi, V. D., Donnard, E., Gellatly, K., Rasmussen, M., Kucukural, A., Yukselen, O., Garber, M., Sharma, U., & Rando, O. J. (2020). An atlas of cell types in the mouse epididymis and vas deferens. eLife, 9, e55474. https://doi.org/10.7554/eLife.55474 Related Episodes The Epigenetics of Human Sperm Cells (Sarah Kimmins) Transgenerational Inheritance and Evolution of Epimutations (Peter Sarkies) The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi) Contact Epigenetics Podcast on X Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Epigenetics Podcast on Threads Active Motif on X Active Motif on LinkedIn Email: podcast@activemotif.com
TWiV discusses effectiveness of this season's flu vaccine, efficacy of Pfizer RSV vaccine, nOPV2 in the US, dengue in Peru, measles in Michigan and Indiana, how coordinated inflammatory responses dictate control of Marburg virus by reservoir bats, and tRNA acquisition in phages driven by degradation of host translational machinery. Hosts: Vincent Racaniello, Rich Condit, Kathy Spindler, Brianne Barker, and Jolene Ramsey Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode MicrobeTV Discord Server MicrobeTV store at Cafepress Become a member of ASV (asv.org) The New City by Dickson Despommier Effectiveness of flu vaccine (MMWR, Eurosurveill) Efficacy of Pfizer RSV vaccine (Pfizer) Understanding six types of vaccine technologies (Pfizer) nOPV in US? (CDC) Dengue in Peru (Peruvian State) Measles in Michigan and Indiana Marburg virus control by reservoir bats (Nat Commun) tRNA acquisition by phages (Cell) Viruses of Microbes 2024 Timestamps by Jolene. Thanks! Weekly Picks Brianne – The reappearance of Lake Manly Kathy – “Practical Playbook for Addressing Health Misinformation” Rich – Making It So: A Memoir by Patrick Stewart Jolene – Thinking Like a Phage by Merry Youle Vincent – The Science of Leap Year Listener Picks Blog design – Anthony Fauci will reflect on his long government career in ‘On Call,' to be published in June Peter – Republican warns of vaccines being slipped into vegetables: ‘A polio vaccine in there' Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv
In this episode of Raising Biotech, Surani explores the untapped world of tRNA therapeutics with Flagship Pioneering-founded company Alltrna. The company raised $109 million in a series B in August 2023. Surani talks to CEO Michelle Werner about the inception of Alltrna, the company's tRNA therapeutic thesis and her journey to the role. She also talks about the company's plans to study its technology in rare genetic liver diseases and the potential to accelerate clinical trials with the use of basket trials. Dr David Weinstein, a rare diseases pediatrician and owner of Weinstein Rare Disease and Clinical Development Consulting also joins the podcast to give his take on the potential of tRNA therapeutics to serve thousands of diseases. He gives his thoughts on the company's mission, potential clinical trial challenges ahead and how the therapeutics might fit into the treatment paradigm.Timestamps:01:58 - Background of Alltrna and tRNA therapeutics for rare genetic diseases06:00 - Company formation under Flagship and Michelle's personal backstory11:35 - Focussing on stop-codon diseases of the liver for first clinical trials12:55 - Dr Weinstein talks about tRNA therapies for rare genetic diseases16:55 - The use of basket trials to accelerate clinical trials 18:30 - Efficacy and safety considerations & regulatory pathway21:45 - How tRNA therapies would fit into the treatment paradigm24:05 - Potential for tRNA in other genetic diseases beyond the liver 26:00 - Alltrna's future pipeline and business strategy For any comments, questions, feedback or suggestions you can connect directly with Surani Fernando on LinkedIn or email: raisingbiotech@gmail.comMusic composed by: Yrii Semchyshyn (Coma Media) Hosted on Acast. See acast.com/privacy for more information.
Today's guests are Theonie Anastassiadis, Co-Founder and Chief Innovation Officer & Stephen Eichhorn, Principal Scientist at Alltrna. Founded in 2018, Alltrna is the world's first tRNA platform company to decipher tRNA biology and pioneer tRNA therapeutics to treat thousands of diseases. The company has an unprecedented opportunity to advance a single tRNA medicine to restore disrupted protein production, regardless of target, for thousands of diseases with the same underlying genetic mutation. Alltrna have successfully applied machine learning to reveal the unique language of tRNA biology. This language is larger than the number of atoms in the universe and turns powerful biology into programmable medicines. Their first-in-field platform integrates learnings across tRNA biology and the modality space to unlock tRNA's full therapeutic potential and design tRNA oligos with desired therapeutic properties. In today's episode, Theonie and Stephen talk about: Their background and journey to now, An overview of Flagship Pioneering, How Alltrna are harnessing tRNA biology for therapeutic medicines, Examples of how their work will improve treatment for patients, The role of AI and Data Science in their platform, What the near future holds for Alltrna, An insight into the team and working culture, What makes Alltrna a great place to work
In this brief episode we explore key questions such as: 1. What if we could use genetic evolution and modifying the ubiquitin-proteasome pathway for more targeted therapy in proteinopathies, for example utilizing directed evolution and protein engineering with ubiquitin or regions of the proteasome complex, to include antisense mRNA for key motifs apart of amyloid precursor protein (APP), PSEN1 or SNCA? Could we better target the histopathological hallmarks associated with Alzheimer's disease, such as the plaques of amyloid-beta, that are indicated in Alzheimer's disease progression?2. What if we could use different modified tRNA, or agents in the protein translation pathway, to facilitate therapy for NDD proteinopathies.In reference to question 1, check out this article on the UPS system in the body: The Ubiquitin–Proteasome System in Immune Cells .
4.11 Antibody Review Rheumatology review for the USMLE Step 1 Exam. ANA Principles ANA (Anti-Nuclear Antibody): Non-specific antibody. Reacts against nuclear antigens, including proteins, DNA, RNA, and nucleic acid-protein complexes. Includes a group of antibodies such as anti-dsDNA, anti-histone, SSA/Ro, SSB/La, Scl-70, anti-aminoacyl-tRNA synthetase (Jo-1). Found in 20-30% of the general public without connective tissue disorder symptoms. ANA+ individuals may or may not have a rheumatologic disorder. Further workup is needed in ANA+ cases to determine the specific disorder. Antibodies by Disease Process Systemic Lupus Erythematosus (SLE) Anti-dsDNA antibody. Anti-Smith antibody. Drug-Induced Lupus Anti-histone antibody. Diffuse vs. Limited Scleroderma Diffuse: Anti-Scl-70 (anti-topoisomerase I). Limited: Anti-centromere (often called CREST syndrome, with CREST standing for centromere). Sjogren's Syndrome Anti-SSA (Ro). Anti-SSB (La), which usually occurs in the presence of SSA. SSA is considered the Sjogren-specific antibody, leading to the presence of SSB. Rheumatoid Arthritis (RA) Anti-CCP (Cyclic Citrullinated Peptide). RF (Rheumatoid Factor) is non-specific. Thanks for listening!
Compared to the smallest mRNA molecule, which is 300 nucleotides long, the largest transfer RNAs (tRNA) is less than a third of the size at 76 nucleotides. Scientists at Alltrna are harnessing the unique biology of tRNAs to engineer a single tRNA medicine that could treat thousands of rare diseases that share the same genetic mutation. This year, Alltrna presented at ASGCT the first demonstration that an engineered, modified tRNA could recognize and correct, in vivo, a flawed mRNA instruction no matter where it occurred in the genome.Alltrna, which was founded in 2018 by Flagship Pioneering, recently announced it had raised $109 million in a Series B financing to advance the company's platform and first drug candidates towards the clinic for a first indication in Stop Codon Disease. Stop Codon Disease encompasses thousands of rare and common diseases that arise from premature termination codons (PTC), also known as nonsense mutations, where the code for an amino acid has been mutated into a premature “stop” codon. This results in a truncated or shortened protein product with no or altered biological activity that causes disease. Approximately 10% of all people with a genetic disease have Stop Codon Disease, representing approximately 30 million people worldwide. Alltrna's tRNA medicines can read these PTC mutations and deliver the desired amino acid, thereby restoring the production of the full-length protein.The company's platform incorporates artificial intelligence and machine learning tools to ‘learn' the tRNA language and deliver diverse, programmable molecules with broad therapeutic potential. This week, our conversation is with Alltrna CEO, Michelle Werner.
Synopsis: Michelle Werner is the CEO of Alltrna and a CEO-Partner at Flagship Pioneering. Alltrna is the world's first tRNA platform company to decipher tRNA biology and pioneer tRNA therapeutics to treat thousands of diseases. Flagship Pioneering conceives, creates, resources, and develops first-in-category bioplatform companies to transform human health and sustainability. Michelle discusses her 20+ year career in drug development and the importance of bringing new innovations to people who need them. She talks about her motivations behind going to business school in London and why she felt she needed to supplement her science and math education with the fundamentals of business in order to transition her career to commercial from R&D. She discusses tRNA as a treatment modality and its potential to be a platform technology. Finally, she shares where the company is from a development perspective and fundraising announcements. Biography: Michelle C. Werner is a seasoned pharmaceutical executive with more than 20 years in the industry spanning both commercial and research & development (R&D) responsibilities. Most recently, Michelle served as Worldwide Franchise Head, Solid Tumors at Novartis Oncology, where she was responsible for delivering the disease area strategies across multiple tumors and led business development efforts resulting in a doubling of long-term portfolio value for the franchise. Previous to Novartis, Michelle was a senior leader at AstraZeneca, where she held multiple positions during her five-year tenure. As Global Franchise Head in Hematology, Michelle was critical in launching multiple indications worldwide for CALQUENCE® and was responsible for developing the mid- and long-term strategy for AstraZeneca in hematology. Prior to this role, Michelle served as Head of US Oncology, where she led the business through dramatic growth in both team and revenue through eight-plus product launches as well as Country President for the Nordics and Baltics, where she also served as an elected Board Member to Sweden's pharmaceutical industry association. Previous to AstraZeneca, Michelle was with Bristol Myers Squibb for 10 years in various positions of increasing responsibility including roles in sales, marketing, and market access in the US and UK, and above market in Europe (based in France) and global almost exclusively in oncology. Michelle started her professional career in R&D, working hands-on with patients at the Oncology Clinical Trials Unit at Harvard Medical School before moving into industry in clinical operations. Outside of her corporate responsibilities, Michelle is a wife and mother to three children and is a member of the rare disease community. She is currently serving a Board appointment for the non-profit organization Rare Disease Renegades, a purpose that fuels her passions both personally and professionally. Michelle holds a B.A. in biology & anthropology from the University of Pennsylvania and an MBA from the London Business School (UK). She also completed an Executive Education program for Women on Boards at Harvard Business School in 2018.
TWiM explains how phages avoid tRNA-targeting host defenses, and discovery of a new antibiotic from an uncultured bacterium that binds to an immutable target. Hosts: Vincent Racaniello, Michael Schmidt, and Petra Levin, Become a patron of TWiM. Links for this episode Phages avoid tRNA-targeting host defenses (eLife) Sea phages Actinobacteriophage database New antibiotic from uncultured bacterium (bioRxiv) The age of infection (For Policy) Killing bacteria by teixobactin (Nature) Take the TWiM Listener survey! Send your microbiology questions and comments (email or recorded audio) to twim@microbe.tv
TWiV dissects a study of COVID-19 vaccination which shows that the timing of initial rollout affects disease outcomes more substantially than final coverage or degree of socioeconomic disparity, and discovery of a novel cellular defense comprising a nuclease that is activated by poxvirus infection and cleaves a specific tRNA molecule to inhibit protein synthesis. Hosts: Vincent Racaniello, Rich Condit, Alan Dove, and Brianne Barker Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode MicrobeTV Discord Server MicrobeTV store at Cafepress Research assistant position in Rosenfeld Lab CBER/FDA (pdf) Impact of COVID-19 vaccination trends (Sci Adv) Poxvirus-activated anticodon nuclease (Sci Adv) Letters read on TWiV 1035 Timestamps by Jolene. Thanks! Weekly Picks Brianne – Project Hail Mary Rich – Bird Buddy Alan – Blood, Sweat, and Pixels and Press Reset Vincent – Are microplastics spreading infectious disease? Listener Picks Tom – Henrietta Lacks family settles lawsuit Kathleen – Why Insect Memories May Not Survive Metamorphosis Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv
Welcome to the Five Song Mixtape! This week we discuss the mixtape titled “Big Wood, Hard Gaze” by Michael. You can find the playlist by following our account on Spotify @FiveSongMixtape or you can find us on Instagram @FiveSongMixtape. We would love to hear your thoughts on the playlist and please give us a rating via iTunes to help spread the word!“Big Wood, Hard Gaze” by Michael1.“Istok” by Trna 2.“Ensomhed” by Sunken3.“I Want to Be There” by Sadness4.“The All-Devouring” by Somn5.“Reborn – Pt. II” by OIhava Hosted on Acast. See acast.com/privacy for more information.
*Royal Truman, PhD: RSR hosts Fred Williams & Doug McBurney welcome Dr. Royal Truman to discuss creation, biology, information science and more! Royal is fluent in five languages and received bachelor's degrees in chemistry and computer science from SUNY Buffalo, an M.B.A from the University of Michigan, his PhD in organic chemistry from Michigan State, with post-graduate studies in bioinformatics at the universities of Mannheim and Heidelberg in Germany. Royal believes the God of Abraham created the universe, and that His Son Jesus Christ is the savior of the world. *Thomas Schneider's Ev: The Punchline: Many evolutionists refer to the work of Thomas Schneider and his Ev program's “proof” that useful information can arise without a creator. Dive into Dr. Truman's refutation of Dr, Schneider's alleged proof that new biological information can arise naturalistically. *Where did the evolutionists go wrong? In simulations they assume that if random mutations changed a protein and / or DNA patterns so that in rare cases they facilitated binding at 1 site this would automatically be selected for! They have this backward. Natural selection would act against finding new binding sites during the non-functional generations. First, statistically virtually all random bindings would be in the wrong places. This messes up the system, creates errors, and wastes resources since proteins could otherwise be used for something useful. Therefore, the competing organisms missing this junk would be better off. Being more fit they would out-populate those doing wasteful nonsense. Correct binding location per se does nothing. If a codon would attach to the right part of the tRNA (the anti-codon region, very unlikely) nothing would happen. ✓ Binding sites need a whole complex machinery to process the code represented by the binding site. Like ribosomes. Or DNA polymerases in the case of genes. ✓ After a transcription factor attaches to a DNA region, it recruits many of exactly the right partner proteins to perform a function. ✓ Often binding sites need to be carefully prepared. Enzymes edit them. Like tRNAs. Otherwise, the 3-nucleotide anti-codon region would not be recognized. New binding sites require new nanomachines which means more DNA (new genes) and more protein. ✓ This slows down the replication time of cells, costs time, energy and material. If a new binding site could arise through random mutations after millions of years, those cells would have long since gotten rid of what was significantly deleterious. Natural selection would work against creating even one new kind of binding site! *The Business of Science: Dr. Truman encourages Christians who have a passion for the sciences to pursue those passions faithfully! Industry needs, (and will hire) scientists who pursue the truth, (even aside from the espousing of the evolutionary worldview). *Chemistry & Computer Science: Hear how a knowledge of information science, in addition to chemistry is essential to understanding and unlocking the potential of binding sites, and why the information involved could not have arisen naturalistically.
*Royal Truman, PhD: RSR hosts Fred Williams & Doug McBurney welcome Dr. Royal Truman to discuss creation, biology, information science and more! Royal is fluent in five languages and received bachelor's degrees in chemistry and computer science from SUNY Buffalo, an M.B.A from the University of Michigan, his PhD in organic chemistry from Michigan State, with post-graduate studies in bioinformatics at the universities of Mannheim and Heidelberg in Germany. Royal believes the God of Abraham created the universe, and that His Son Jesus Christ is the savior of the world. *Thomas Schneider's Ev: The Punchline: Many evolutionists refer to the work of Thomas Schneider and his Ev program's “proof” that useful information can arise without a creator. Dive into Dr. Truman's refutation of Dr, Schneider's alleged proof that new biological information can arise naturalistically. *Where did the evolutionists go wrong? In simulations they assume that if random mutations changed a protein and / or DNA patterns so that in rare cases they facilitated binding at 1 site this would automatically be selected for! They have this backward. Natural selection would act against finding new binding sites during the non-functional generations. First, statistically virtually all random bindings would be in the wrong places. This messes up the system, creates errors, and wastes resources since proteins could otherwise be used for something useful. Therefore, the competing organisms missing this junk would be better off. Being more fit they would out-populate those doing wasteful nonsense. Correct binding location per se does nothing. If a codon would attach to the right part of the tRNA (the anti-codon region, very unlikely) nothing would happen. ✓ Binding sites need a whole complex machinery to process the code represented by the binding site. Like ribosomes. Or DNA polymerases in the case of genes. ✓ After a transcription factor attaches to a DNA region, it recruits many of exactly the right partner proteins to perform a function. ✓ Often binding sites need to be carefully prepared. Enzymes edit them. Like tRNAs. Otherwise, the 3-nucleotide anti-codon region would not be recognized. New binding sites require new nanomachines which means more DNA (new genes) and more protein. ✓ This slows down the replication time of cells, costs time, energy and material. If a new binding site could arise through random mutations after millions of years, those cells would have long since gotten rid of what was significantly deleterious. Natural selection would work against creating even one new kind of binding site! *The Business of Science: Dr. Truman encourages Christians who have a passion for the sciences to pursue those passions faithfully! Industry needs, (and will hire) scientists who pursue the truth, (even aside from the espousing of the evolutionary worldview). *Chemistry & Computer Science: Hear how a knowledge of information science, in addition to chemistry is essential to understanding and unlocking the potential of binding sites, and why the information involved could not have arisen naturalistically.
*Royal Truman, PhD: RSR hosts Fred Williams & Doug McBurney welcome Dr. Royal Truman to discuss creation, biology, information science and more! Royal is fluent in five languages and received bachelor's degrees in chemistry and computer science from SUNY Buffalo, an M.B.A from the University of Michigan, his PhD in organic chemistry from Michigan State, with post-graduate studies in bioinformatics at the universities of Mannheim and Heidelberg in Germany. Royal believes the God of Abraham created the universe recently, and that His Son Jesus Christ is the savior of the world. *Ties that Bind: What is a binding site? The dictionary definition: “a region on a molecule or cell surface at which the combining of chemical substances takes place,” is elaborated upon by Dr. Truman as to sophistication, logic, instruction, and the precise nature of the information involved in the combining, (proving that the “binding” is far more than a mere “combining of chemical substances”), it's the actuation of potential via informational code! *Information & Chemistry: Dr. Truman connects the regulating activities occurring in genes & cells, with how understanding information science is helpful in solving the chemistry problems associated with the study of biological systems. Finding binding sites is important to advancing our knowledge of biological systems, cells and genetics. Hear how information science unlocks the search for binding sites. And then hear about how they work! How 3 nucleotides, codons on (messenger) mRNA interact exactly with their 3 counterparts on (transcription) tRNA - anticodons, (and so much more). *Smarts, Schools, & Worldview: Hear Dr. Truman give a couple thoughts on how worldview is influenced by education, and especially higher education. *Calling Dr. Schneider: Dr. Truman invites Dr. Thomas Schneider to work together with him in areas where they agree, and may be able to help one another, and the world better understand reality and the truth.
*Royal Truman, PhD: RSR hosts Fred Williams & Doug McBurney welcome Dr. Royal Truman to discuss creation, biology, information science and more! Royal is fluent in five languages and received bachelor's degrees in chemistry and computer science from SUNY Buffalo, an M.B.A from the University of Michigan, his PhD in organic chemistry from Michigan State, with post-graduate studies in bioinformatics at the universities of Mannheim and Heidelberg in Germany. Royal believes the God of Abraham created the universe recently, and that His Son Jesus Christ is the savior of the world. *Ties that Bind: What is a binding site? The dictionary definition: “a region on a molecule or cell surface at which the combining of chemical substances takes place,” is elaborated upon by Dr. Truman as to sophistication, logic, instruction, and the precise nature of the information involved in the combining, (proving that the “binding” is far more than a mere “combining of chemical substances”), it's the actuation of potential via informational code! *Information & Chemistry: Dr. Truman connects the regulating activities occurring in genes & cells, with how understanding information science is helpful in solving the chemistry problems associated with the study of biological systems. Finding binding sites is important to advancing our knowledge of biological systems, cells and genetics. Hear how information science unlocks the search for binding sites. And then hear about how they work! How 3 nucleotides, codons on (messenger) mRNA interact exactly with their 3 counterparts on (transcription) tRNA - anticodons, (and so much more). *Smarts, Schools, & Worldview: Hear Dr. Truman give a couple thoughts on how worldview is influenced by education, and especially higher education. *Calling Dr. Schneider: Dr. Truman invites Dr. Thomas Schneider to work together with him in areas where they agree, and may be able to help one another, and the world better understand reality and the truth.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.09.536152v1?rss=1 Authors: Rhymes, E. R., Simkin, R. L., Surana, S. N., Tong, Y., Villarroel-Campos, D., Yang, X.-L., Schiavo, G., Sleigh, J. N. Abstract: Charcot-Marie-Tooth disease (CMT) is a form of genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which charge amino acids to partner tRNAs for protein synthesis, represent the largest protein family linked to CMT aetiology, suggestive of pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for CMT type 2D (CMT2D)-causing mutant glycyl-tRNA synthetase. We then performed temporal neuromuscular assessments of recently generated YarsE196K mice modelling DI-CMT. Through in vivo imaging of exposed sciatic nerves, we determined that YarsE196K homozygotes display a selective, age-dependent impairment in axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. Increasing BDNF in DI-CMTC mouse muscle, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a pathomechanism common to neuropathies caused by mutations in YARS1 and GARS1, and highlights the potential of boosting BDNF in muscles as a therapeutic strategy to treat ARS-related CMTs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Die Metamorphose der Renate - Der Weg zum Protein ist fast geschafft. Die Informationen sind herausgearbeitet und müssen nur noch übersetzt werden. Dieser Aufgabe widmen sich die Ribosom und zu gleich auch diese Folge! Neben der RNA-Prozessierung und dem Spleißen nehmen wir uns heute endlich die Translation vor und vollenden die Metamorphose! (00:00) - RNA-Prozessierung und Splicing (13:49) - Aufbau Ribosom und tRNA (26:48) - Ablauf der Translation Für die Inhalte in diesem Podcast übernehmen wir keine Gewähr. Der Podcast kann den Besuch von Vorlesungen nicht ersetzen. Wir empfehlen das Studium von einschlägiger Fachliteratur über den Inhalt des Podcasts hinaus.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.26.534279v1?rss=1 Authors: Meineke, B., Heimgärtner, J., Caridha, R., Block, M., Kimler, K. J., Pires, M. F., Landreh, M., Elsässer, S. J. Abstract: Genetic code expansion via stop codon suppression is a powerful strategy to engineer proteins. Suppressor tRNAs are aminoacylated with noncanonical amino acids (ncAAs) by dedicated aminoacyl-tRNA synthetases (aaRS) and direct ncAA incorporation site-specifically during translation. These pairs of tRNA/aaRS must be orthogonal to the host's tRNAs, aaRS and natural amino acids. Pyrrolysyl-tRNA (PylT)/PylRS pairs from methanogenic archaea, as well as engineered tRNA/aaRS pairs derived from bacteria, are used for genetic code expansion in mammalian cells. Amber suppression is routinely achieved by transient introduction of the components leading to short-term and heterogeneous expression. Here, we demonstrate that stable integration of tRNA/aaRS genes allows for efficient, genetically encoded ncAA incorporation in diverse mammalian cell lines. We extend a general plasmid design and PiggyBac (PB) integration strategy developed for the Methanosarcina mazei PylT/PylRS pair to genomic integration of two tRNA/aaRS pairs of bacterial origin. We further explore suppression of ochre and opal stop codons and parallel incorporation of two distinct ncAAs, both accessible for click chemistry, by dual suppression in stable cell lines. Clonal selection allows for isolation of cells with high dual suppression efficiency and dual site-specific fluorescent labeling of a cell surface receptor using bioorthogonal click chemistries on live mammalian cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.23.533914v1?rss=1 Authors: Fedry, J., Silva, J., Vanevic, M., Fronik, S., Mechulam, Y., Schmitt, E., des Georges, A., Faller, W., Förster, F. Abstract: Aberrantly slow mRNA translation leads to ribosome stalling and subsequent collision with the trailing neighbor. Ribosome collisions have recently been shown to act as stress sensors in the cell, with the ability to trigger stress responses balancing survival and apoptotic cell-fate decisions depending on the stress level. However, we lack a molecular understanding of the reorganization of translation processes over time in mammalian cells exposed to an unresolved collision stress. Here we visualize the effect of a persistent collision stress on translation using in situ cryo electron tomography. We observe that low dose anisomycin collision stress leads to the stabilization of Z-site bound tRNA on elongating 80S ribosomes, as well as to the accumulation of an off-pathway 80S complex possibly resulting from collision splitting events. We visualize collided disomes in situ, occurring on compressed polysomes and revealing a stabilized geometry involving the Z-tRNA and L1 stalk on the stalled ribosome, and eEF2 bound to its collided rotated-2 neighbor. In addition, non-functional post-splitting 60S complexes accumulate in the stressed cells, indicating a limiting Ribosome associated Quality Control clearing rate. Finally, we observe the apparition of tRNA-bound aberrant 40S complexes shifting with the stress timepoint, suggesting a succession of different initiation inhibition mechanisms over time. Altogether, our work visualizes the changes of translation complexes under persistent collision stress in mammalian cells, indicating how perturbations in initiation, elongation and quality control processes contribute to an overall reduced protein synthesis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.05.531223v1?rss=1 Authors: Morishima, T., Fakruddin, M., Masuda, T., Wang, Y., Schoonenberg, V. A. C., Butter, F., Arima, Y., Akaike, T., Tomizawa, K., Wei, F., Suda, T., Takizawa, H. Abstract: A lack of the mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) was recently shown to induce proteostress in embryonic stem cells. Since erythroid precursors actively synthesize the hemoglobin protein, we hypothesized that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complex-I was severely defective in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis and enhanced the expression of embryonic hemoglobin proteins, which induced an unfolded protein response via the IRE1 -Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Gurdjieff: Cosmic Secrets - the Teaching Guide: Exercises and Talks
We are publishing the entire seven chapters of The Blueprint of Consciousness Audiobook, excluding the Objective Exercise (you will need to purchase the book for that). This podcast is part 4 of Chapter 4 of the audiobook of The Blueprint of Consciousness. In this episode we show how the harmonically stable oscillations in an octave may actually form the tRNA molecules that help to create life, and how the mathematical symmetry inherent within an octave ensures perfect replication. The podcast episode page can be found here on our website thedogteachings.com. Our high-quality 520 page hardback, entitled The Blueprint of Consciousness, is now available for order and study - an 8 day journey to awakening with exercises to work on being, and seven chapters explaining the diatonic nature of the universe, with an ultimate exercise to objectively awaken. Available here. --- Send in a voice message: https://anchor.fm/thedogteachings/message Support this podcast: https://anchor.fm/thedogteachings/support
Nels and Vincent discuss how evolution of changes in stop codon assignment might occur, and a novel mechanism for altering the meaning of translation stop codons discovered in a trypanosomatid with the apropos name, Blastocrithidia nonstop. Hosts: Nels Elde and Vincent Racaniello Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiEVO Links for this episode •Join the MicrobeTV Discord server •Novel stop codon reassignment mechanisms (Nature) Science Picks Nels – Protein Synthesis: An epic on the cellular level Vincent – Widespread stop-codon recoding in bacteriophages may regulate translation of lytic genes discussed on TWiM 277 Music on TWiEVO is performed by Trampled by Turtles Send your evolution questions and comments to twievo@microbe.tv
A new autoantibody to valyl transfer RNA synthetase associated with anti-synthetase syndrome Dr Tsuneo Sasai and Dr Ran Nakashima (both Kyoto University Graduate School of Medicine, Japan) join Dr Latika Gupta to discuss a 43-year-old male patient clinically diagnosed with anti-synthetase syndrome but lacking any known disease-specific autoantibodies. They identify a new autoantibody directed against valyl tRNA synthetase and highlight the importance of identifying more such cases to identify clinical characteristics. You can read this article in Rheumatology. Thanks for listening to Talking Rheumatology Research! Join the conversation on Twitter using #TalkingRheumResearch, tweet us @RheumJnl, or find us on Instagram. Want to read more rheumatology research? Explore Rheumatology and Rheumatology Advances in Practice.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.30.522321v1?rss=1 Authors: Hogan, C. A., Gratz, S. J., Dumouchel, J. M., Delgado, A., Lentini, J. M., Madhwani, K. R., Thakur, R. S., Fu, D., O'Connor-Giles, K. M. Abstract: Nervous system function relies on the formation and function of synaptic connections between neurons. Through a genetic screen in fDrosophila for new conserved synaptic genes, we identified CG42261/Fid/ TRMT9B as a negative regulator of synaptogenesis. TRMT9B has been studied for its role as a tumor suppressor in multiple carcinomas and is one of two metazoan homologs of yeast tRNA methyltransferase 9 (Trm9), which methylates tRNA wobble uridines. Members of the expanded family of tRNA methyltransferases are increasingly being associated with neurological disorders and new biochemical functions. Interestingly, whereas Trm9 homolog ALKBH8/CG17807 is ubiquitously expressed, we find that TRMT9B is enriched in the nervous system, including at synapses. However, in the absence of animal models the role of TRMT9B in the nervous system has remained unknown. Here, we generated null alleles of TRMT9B and ALKBH8, and through liquid chromatography-mass spectrometry find that ALKBH8 is responsible for canonical tRNA wobble uridine methylation under basal conditions. In the nervous system, we find that TRMT9B negatively regulates synaptogenesis through a methyltransferase-dependent mechanism in agreement with our modeling studies. Finally, we find that neurotransmitter release is impaired in TRMT9B mutants. Our findings reveal a role for TRMT9B in regulating synapse formation and function, and highlight the importance of the expanded family of tRNA methyltransferases in the nervous system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Kosuke Fujishimaさんをゲストに迎え、これまでの研究人生に触れながら研究雑談しました。Shownotes このShownotesは藤島さんからのコメント・修正を受ける前です。またコメント・修正を受け取り次第更新いたしますのでご了承ください。 (by tadasu) Kosuke Fujishima Fujishimaさんの一つ前のエピソード テラフォーマーズ 冥王代 tri-split tRNA RNA world仮説 目ブラスト 貴家悠 藤島さんと貴家さんの対談 高井研 vs 貴家さん 減数分裂 東京喰種トーキョーグール レベルE 44. XXXXXYYYYY (Researchat.fm) … レベルE解説エピソード Lynn J. Rothschild 火星のマグマは噴出するか？ … Nature Geo Science? 火星の海 テラフォーマーズ20巻 … どこに藤島さんいるのか正直特定できておりません… ロスチャイルド家 エンケラドゥス 質量分析 衝突マス Eリング decadal survey from NASA 高速衝突実験装置 ISS アストロバイオロジーの三大研究 … 生命の起源、生命の分布、人類の宇宙進出 東大の工藤先生 全自動メダカ飼育装置 宇宙メダカの論文 宇宙メダカ選抜テスト 某ショット … 人類は月には何年前に到達したんだっけ？ ケンタウルス座アルファ星 ブレイクスルー財団 鉛の板 Yuri Milner ブレイクスルースターショット計画 イーロン・マスク … ep19 Neuron Maskを参照のこと SpaceX The Martian … いわゆるオデッセイ Andy Weir 過塩素酸 Soda Lakes 過塩素酸入り培地で育つ微生物 ATGCU … DNA/RNAの塩基 111. Mirror Image Biology … 鏡像異性体の回 鏡像異性体は味がするのか？ ラセミ化 深海の微生物にはラセマーゼが多い ホモキラル EBI … European Bioinformatics Institute Joana Pereira タンパク質の配列空間 … よく使うフレーズなのですが、適切な名前が思い浮かばない (tamaki) ふじしまさんが載っているJAXAの宇宙飛行士募集ページ … 「宇宙飛行士に転職だ」 宇宙飛行士選抜テスト こまささん … 藤島さんのお友達 「大西宇宙飛行士に、OB訪問だ。」JAXA宇宙飛行士候補者募集スペシャルムービー … ふじしまさんがOB訪問という形で大西宇宙飛行士インタビューしています Editorial Notes (fujishi) 実は今回は高校生の皆さんにリーチするという野望があったのですが、届いたのだろうか・・・(coela) おもしろすぎました。完全版shownotesはそのうちに(tadasu)
Kosuke Fujishimaさんをゲストに迎え、アストロバイオロジー、生命の起源などについて話しました。Shownotes このShownotesは藤島さんからのコメント・修正を受ける前です。またコメント・修正を受け取り次第更新いたしますのでご了承ください。 (by tadasu) Kosuke Fujishima Kosuke Fujishima@Twitter Kosuke Fujishimaさんがバイリンガルニュースに出た回 アストロバイオロジー … 宇宙生物学 アストロバイオロジー 米国航空宇宙局（NASA）エクソバイオロジーとアストロバイオロジーの歴史 … アストロバイオロジーの説明漫画 NASA ESLI SFC … 慶應義塾大学湘南藤沢キャンパス 冨田勝 金井明夫 アーキア(古細菌) RNA 藤島さんのtri-split tRNAの論文 … “Tri-split tRNA is a transfer RNA made from 3 transcripts that provides insight into the evolution of fragmented tRNAs in archaea” 別々に転写された3つのパーツからｔRNAが合体して機能する！！ 慶應義塾大学先端生命科学研究所 海外学振 あのクマムシ博士 … クマムシ博士、我々はいつでも出演していただけるのを待っております！(by Researchat.fm一同) クマムシ博士の「最強生物」学講座 私が愛した生きものたち クマムシ?!―小さな怪物 AMES Research Center クマムシさん 腸内細菌 リボソーム … 高校生物IIでは習うはずです by tadasu 細胞はリボソームを作るマシーンである RNA, アミノ酸、タンパク質、それぞれの構造の複雑さと組み合わせの複雑さ、そして粒度などなどを考えていく必要がありますね (by tadasu) 翻訳 … セントラルドグマの方のやつ リボソームRNA tRNA アミノ酸 分子生物学 スーパーサイエンスハイスクール(SSH) バイオサミット ミトコンドリア ネアンデルタール人 … ノーベル賞取った！ シアノバクテリア LUCA以前の話とネアンデルタール人、隕石とかの話はごちゃごちゃにするとわかりにくい気がする。そもそもその時代の選択圧とは。 進化の特異事象 … この本を再履修するか… (by tadasu) 深海熱水噴出孔 バキ … 柳は死刑囚編に登場 柳龍光 … 「この地球上で最も強力な毒ガスとは何かわかるかね？」 クローバーリーフ構造 … tRNAの取る二次構造 コドン 原始代謝系 グリシン Alpha helix Beta sheet LUCA … Last universal common ancestor 冥王代 はやぶさ pre-biotic chemistry ユーリー・ミラーの実験 デカフェ ハーデース … ギリシャ神話は聖闘士星矢とFGOで勉強しました by coela 外惑星 JAXA 超臨界 JAMSTEC しんかい6500 アスガルド古細菌 高井研 … 大尊敬する大先生 ケプラーミッション ハッブル ウェッブ Craig Venter Mycoplasma laboratorium Synthetic Biology アストロバイオロジーキャンプ - たとえcoela氏が大学入学前に情報を持っていたとしても何もしていないんじゃないかなぁ by tadasu Editorial Notes どんどん話題が移り変わっていく感じで自由に話すことができて非常に楽しかったです。若年リスナーの好奇心を少しでも刺激できているといいな。(fujishi) 藤島さん出演ありがとうございます！！！ロマンがある話がたくさんできて楽しかったです。(coela)
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.13.512020v1?rss=1 Authors: Kagermeier, T., Hauser, S., Sarieva, K., Laugwitz, L., Groeschel, S., Janzarik, W., Yentuer, Z., Becker, K., Schoels, L., Kraegeloh-Mann, I., Mayer, S. Abstract: Pontocerebellar hypoplasia type 2 a (PCH2a) is a rare, autosomal recessive neurogenetic disorder. Affected individuals present with early and severe neurological impairment. The anatomical hallmark of PCH2a is the hypoplasia of the cerebellum and pons accompanied by progressive microcephaly over the first years of life (OMIM #277470). Treatment options are limited and symptomatic. PCH2a results from a homozygous founder variant in the TSEN54 gene (OMIM *608755), which encodes a tRNA splicing endonuclease complex subunit. A recent study revealed altered tRNA pools in fibroblasts from affected individuals with PCH2a. However, the pathological mechanism underlying the hypoplasia of the cerebellum and the progressive microcephaly is unknown due to a lack of a model system. Leveraging recent progress in organoid generation, we developed human models of PCH2a using brain region-specific organoids. We, therefore, obtained skin biopsies from three affected males with genetically confirmed PCH2a and derived induced pluripotent stem cells (iPSCs). Cerebellar and neocortical organoids were differentiated from control and affected iPSCs and showed expression of TSEN54. In line with neuroimaging findings in affected individuals, PCH2a cerebellar organoids are reduced in size compared to controls starting early in differentiation. While neocortical PCH2a organoids also show growth deficits, they are less pronounced than those in cerebellar organoids, reminiscent of the progressive microcephaly in PCH2a. In addition, we do not find evidence of increased apoptosis in PCH2a organoids compared to controls in contrast to what has been suggested in loss-of-function animal models. We have generated a human model of PCH2a, which will allow to decipher disease mechanisms in depth in order to explain how a variant in a ubiquitously expressed gene involved in tRNA metabolism causes pathology in specific brain regions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Michelle Werner, CEO Partner of Flagship Pioneering and CEO of Alltrna, joins Hafiz Sikder to discuss her work and role at Alltrna as well as her personal investment in the field. She dives deep into the impact of tRNA on drug development, premature stop codons, and her drive to do more for rare disease.
Lovisa Afzelius is an origination partner at Flagship Pioneering and the former SVP of Strategy & Operations at Flagship-founded Cogen Immune Medicines, now known as Repertoire Immune Medicines. A computational scientist by training, she has two decades of leadership experience and a passion for data-driven drug discovery, from early inception to clinical development across multiple therapeutic areas. Previously, Lovisa built and led Pfizer's systems immunology function and served as executive director of clinical programs. In this role, she launched several Phase II studies across autoimmune indications and as a member of the Inflammation & Immunology Research Unit leadership team, Lovisa co-managed the portfolio from early target discovery to Phase II clinical trials across all immunological assets. In addition, she served on Pfizer's Worldwide R&D Data Strategy Committee. In 2017, Lovisa co-founded Elsa.science, a digital health company in the rheumatoid arthritis space where she serves as chairman of the board. She also serves on the board of the Swedish New England Chamber of Commerce. Before moving to the US in 2013, Lovisa was CEO of BioChromix Pharma. Lovisa began her career at AstraZeneca as Project Director, Global In Vitro Metabolism Leader and Computational Chemist across cardiovascular, metabolic, and neurodegenerative diseases. Lovisa has received numerous accolades for her work: she was included in the top 100 “most influential persons under age 40 in Sweden” by Affärsvärlden, and “scientist of tomorrow” at the European Federation of Pharmaceutical Industries and Associations' 30th anniversary. Lovisa received the Rosenön Award for best thesis of the year within the field of pharmacodynamics/pharmacokinetics in Sweden. Lovisa holds a Ph.D. in computational chemistry from Uppsala University, a Master of Science in integrative pharmacology from Gothenburg University as well as an M.B.A. from the MIT Sloan School of Management. Theonie is a principal at Flagship Pioneering where she conceives, builds and grows the science, intellectual property and business strategy that form the foundation of Flagship's next breakthrough startups. She co-founded Alltrna and serves as its chief innovation officer. Prior to joining Flagship, Theonie completed her graduate studies in cell and molecular biology at the Perelman School of Medicine at the University of Pennsylvania. Her research focused on replication fork dynamics in the context of cancer development and therapeutics. Theonie has received several awards and has been granted multiple fellowships for her academic work, including an NIH NRSA Predoctoral Fellowship. During her graduate studies, Theonie held multiple leadership positions on Executive and Curriculum Committees. She also completed a Wharton Business Foundations Specialization and was a mentor at the yearly Larta Institute NIH CAP FeedForward Sessions. Theonie is a Business Advisory Board member of the Harvard Institute for RNA Medicine and a member of the Bioscience & Investor Inclusion Group (BIIG) Diverse Talent Network Group. Theonie's work has resulted in multiple pending patents and publications, including articles in Nature Biotechnology, Molecular Cell and Journal of Biological Chemistry.
00:00:00 - Joe and Ryan are joined by their friend Dr. Antonio “Tony” Munoz, who tells us about his work as a scientist and his journey from the world of research to the world of consulting. Tony's open access papers for those who want to learn more: Free energy calculation of modified base-pair formation in explicit solvent: A predictive model Active yeast ribosome preparation using monolithic anion exchange chromatography Structural Changes Enable Start Codon Recognition by the Eukaryotic Translation Initiation Complex Conserved residues in yeast initiator tRNA calibrate initiation accuracy by regulating preinitiation complex stability at the start codon Coordinated Movements of Eukaryotic Translation Initiation Factors eIF1, eIF1A, and eIF5 Trigger Phosphate Release from eIF2 in Response to Start Codon Recognition by the Ribosomal Preinitiation Complex 00:36:38 - Joe managed to bring drinks for everyone, but now they're not in the same place so that's odd. Joe is having some homemade mead from a friend, and its first mead experience which incurs the cost of viking toast. And Tony and Ryan are enjoying the Snakeden Saison from 7 Locks Brewing as provided by Joe. 01:10:59 - In our second segment we talk about cars. A sort of “Car Talk”, if you will, which we're pretty sure is a completely original idea to the audio format. We tackle the myth that electric cars are actually worse for the environment than internal combustion (spoiler: they're not) , but also some of the challenges that come with an electric future and the impact that our need for certain minerals can have on the health of the planet. 01:56:48 - PaleoPOWs are a lot like roads, you should look both ways before crossing them. Joe has a tweet lauding him for comparing the UK to TX, but what we're really here from is to hand out a BSso thesis for Patron Eric P. He has a thesis titled: Swinging for the electric fences: An electric vehicle charging solution utilizing molecular biophysical properties of Electrophorus fish in an in situ aquatic reservoir. Thanks, Eric! More cool rewards await you if you decide to support us on our Patreon! Music credit: Electric Car - Podington Bear Audio Production: Rob Heath
In this episode, we review the high-yield topic of tRNA from the Biochemistry section. Follow Medbullets on social media: Facebook: www.facebook.com/medbullets Instagram: www.instagram.com/medbulletsofficial Twitter: www.twitter.com/medbullets --- Send in a voice message: https://anchor.fm/medbulletsstep1/message
Ariel Frame and Elizabeth Mohler speak with Brendan Charles about his research on Drosophila melanogaster (fruit flies) investigating how these animals behave and how they can be used to study the biology of the brain. In particular, Brendan discusses work from his recently completed MSc and ongoing PhD work that touches on 9 neurons in the fly brain which govern female aggressive behaviour and characterization of tRNA mistranslation in flies. To learn more about this kind of fly research, check out Dr. Amanda Moehring's Twitter @FlyBehaviour and website. Recorded on Oct 6, 2021 Produced by Ariel Frame Theme song provided by https://freebeats.io/ Produced by White Hot.
Revues et podcasts hebdomadaire en direct ! Venez nous voir ! Site web: https://beacons.ai/mindedmetal Facebook: https://www.facebook.com/MetalMindedCan Instagram: https://www.instagram.com/mindedmetal/ Twitter: https://twitter.com/MindedMetal Spotify: https://open.spotify.com/show/14BH6eJjqqyLEUGRNriwTL Discord: https://discord.gg/S8aGTEj Nos partenaires : Horreur FM: https://www.youtube.com/channel/UCKVHDSO6WOIoqbs5V6oIdIQ Melogy Musicraft: https://www.melogymusicraft.com Boutique Broue HAHA: https://brouehaha.com À la dérive brasserie artisanale: https://aladerivebrasserieartisanale.ca Cordonnerie chez Gerry: https://cordonneriechezgerry.ca Le Fanzine Crypt of Dr. Gore: https://cryptofdrgore.wordpress.com --- Send in a voice message: https://podcasters.spotify.com/pod/show/metalmindedpodcast/message
Animée par Jeff et Eric Melkiahn avec Paz et Clément L'humeur est au death metal pour une large partie de l'émission puisqu'en plus des dernières chroniques écrites déjà disponibles de The Work de RIVERS OF NIHIL et Torn Arteries des incontournables CARCASS, nous proposons ce soir un focus sur ces nouvelles œuvres dans la partie thématique de notre émission qui sera animée par quatre voix. La première heure ne sera pas en reste avec une partie playlist toujours éclectique proposant des promenades dans les sentiers sinistres du funeral doom au post-metal en passant par le black metal atmosphérique… Elle propose cette semaine des extraits des nouveaux albums de SKEPTICISM, DAWN FADES, TRNA, INFERI et ISKANDR.
aTyr Pharma (LIFE) is a biotherapeutics company that researches extracellular functionality and signaling pathways of tRNA synthetases. Oppenheimer recently raised price target on the stock to $20 as it is up 132% this year. Next, Lion Electric (LEV) stock shares are up 14% this week. This company is a maker of electric commercial vehicles. The final stock that George Tsilis discusses is Hut 8 Mining (HUT) with shares up 277% this year.
The Night Flight Orchestra (who are very camp) did a video earlier this year which was clearly pro-LGBT+. Which meant Hell Bent For Metal (also camp) had to talk to them. So this week, NFO's David Andersson (also of Soilwork) speaks to Matt about showing your support for the LGBT+ community, embracing the camp, and the joy of a big gay chorus.Vallenfyre's 2011 debut album, A Fragile King, has a special place in Tom's heart thanks to his history with it. And despite knowing precisely what it's about, the song 'Desecration' has taken on a very queer-specific meaning in his head. He and Matt chat about why.Plus this week's additions for the Hate Crew Gaybar jukebox are the new EP from Ukrainian jazz/black metal band White Ward, and Istok, the latest album by Russian shoegazy black metal band Trna.
Eine weitere Grundwissen-Folge erwartet dich hier. Schau gerne im Skript nach: HIER. Abonniere @biologopodcast auf Instagram - hier findest du ebenfalls die entsprechenden Links. Bewerte den Podcast auf applepodcast oder iTunes. Wichtige Fachbegriffe: Doppelhelix, komplementär, antiparallel, Proteinbiosynthese, 3' und 5'-Ende, Adenin, Guanin, Cytosin, Thymin, Uracil, RNA, mRNA, tRNA, rRNA, Ribosom, ...
My AP Biology Thoughts Unit 6 Gene Expression and RegulationWelcome to My AP Biology Thoughts podcast, my name is Shriya Karthikvatsan and I am your host for episode #110 called Unit 6: Gene Expression and Regulation. Today we will be discussing the mechanisms used by cells to increase or decrease the production of specific gene types, and how this fits into the overarching unit. Segment 1: Introduction to Gene Expression and RegulationWe will begin by going over a few helpful terms and ideas to provide context for the topic of gene expression and regulation which is a pretty broad topic as a whole A gene consists of a string of DNA hidden in a cell's nucleus, and what we will unpack is how it knows when to express itself and cause the production of a string of amino acids called a protein The overall process is that a string of DNA is expressed to make RNA Then, something called mRNA is translated from nucleic acid coding to protein coding to form a protein In terms of regulation, genes can't control an organism on their own so they must interact with and respond to the organism's environment Some genes are always “on” regardless of environmental conditions, and these genes are among the most important elements of the genome because they control the ability of DNA to replicate, express itself, repair itself, and perform protein synthesis Overall, regulated genes are needed occasionally and get turned “on” or “off” Regulation differs between prokaryotes and eukaryotes because in prokaryotes, most regulatory proteins are negative and turn genes off In eukaryotes, cell-cell differences are determined by expression of different sets of genes This means that an undifferentiated fertilized egg looks and acts quite different from a skin cell, a neuron, or a muscle cell because of differences in the genes each cell expresses In the next segment we will go into further detail of the specific processes involved in expression and regulation Segment 2: More About Gene Expression and RegulationGene expression begins with transcription which makes mRNA and the overall process is the same in both prokaryotes and eukaryotes Prokaryotes lack a nuclear envelope, and eukaryotes use an extra step called RNA processing where RNA is edited and introns are edited out and exons are spliced together It is catalyzed by RNA polymerase which separates DNA strands and links RNA nucleotides at the 3' end (side notes: prokaryotes have 1 type of polymerase and eukaryotes have 3) Transcription is initiated when RNA polymerase binds to a promoter and unwinds the DNA strands Initiation site and a small sequence after are recognized by transcription factors which are proteins that bind to promoter and guide RNA polymerase to bind to TATA box Then, mRNA carries the genetic code and mRNA itself is a series of codons In eukaryotes, mRNA processing works by the 5' end getting a GTP cap and the 3' end getting a poly-A tail Also, a splicesome complex of SnRNPs + a protein work together to cut out the introns (intruding codons) and splice the exons (expressed codons) together Following transcription, translation occurs in the ribosome after mRNA brings the genetic code and it is when tRNA brings the amino acid and the ribosome is able to be completely assembled Translation is initiated by a small subunit of the ribosome which binds to a recognition site on the mRNA and an anticodon of tRNA initiator binds to a start codon The next part of translation is elongation in which the anticodon of the next tRNA binds to a codon at the A site and the polypeptide bonds the 2nd amino acid onto the 1st amino acid (this process repeats until a stop codon is reached) Finally, termination is when the stop codon reaches the A site and a release factor frees the tRNA from the P site and disconnects the polypeptide causing everything to separate After translation, the protein is modified
My AP Biology Thoughts Unit 6 Gene Expression and RegulationWelcome to My AP Biology Thoughts podcast, my name is Saarim Rizavi and I am your host for episode #108 called Unit 6 Gene Expression and Regulation: Translation. Today we will be discussing everything there is to know about translation. I will first be giving a brief overview of what translation is, it's overall function, the 3 steps involved in translation, and some of the different components and organelles involved in translation. I'll then go into greater detail on the individual steps of translation which will involve the organelles and different components mentioned before. Finally, I will relate the process of translation to the broader topic of gene expression and regulation. Before I begin, I would like to give credit to Khan Academy, biologydictionary.com, and nature.com for the information they provided me with in order for this podcast to be possible. So thanks to them. Alright, so here we go: Segment 1: Introduction to TranslationTranslation is the process of creating proteins from an mRNA template A cell reads information from mRNA molecules and uses this information to build a protein - involves decoding an mRNA and using its information to build a polypeptide, and multiple polypeptide chains form a protein Three basic steps of translation - initiation, elongation, and termination Initiation - the ribosomes get together with the mRNA and the first tRNA so translation can begin Elongation - the amino acids are brought to the ribosome by tRNAs and linked together to form a chain of amino acids Termination - the finished polypeptide is released to go and do its job in the cell In mRNA, the instructions for building a polypeptide come in groups of 3 nucleotides called codons - there are 61 codons for amino acids and each of them is read to specify a certain amino acid out of the 20 possible amino acids Stop codons tell the cell when polypeptide is complete and the AUG codon is the start codon which signals the start of protein construction In translation, the codons of an mRNA are read in order, from the 5' end to the 3' end, by tRNAs. tRNA's = molecular bridges that connect mRNA codons to the amino acid they encode One end of the tRNA has a sequence of 3 nucleotides called an anticodon, which binds to a matching mRNA codon through base pairing; the other end of the tRNA carries the amino acid specified by the codons tRNAs bind to mRNAs inside the ribosomes - ribosomes are made up of protein and ribosomal RNA The ribosomes provide a set of slots where tRNAs can find their matching codons on the mRNA template and deliver their amino acids. As these tRNAs enter slots in the ribosome and bind to codons, their amino acids are linked to the growing polypeptide chain in a chemical reaction. Segment 2: More About Translation Initiation Ribosome, an mRNA with instructions for the protein to be built, and an initiator tRNA carrying the first amino acid in the protein - these components come together to form the initiation complex which is the molecular setup needed to make a new protein The tRNA carrying the methionine attaches to the small ribosomal subunit - they bind to the 5' end of the mRNA by recognizing the 5' GTP cap which was added during processing in the nucleus They go along the mRNA in the 3' direction, stopping when they reach the start codon (eukaryotic cells) In bacteria, the small ribosomal subunit attaches directly to certain sequences in the mRNA - these Shine-Dalgarno sequences mark the start of each coding sequence, letting the ribosome find the right start codon for each gene. Elongation The amino acid chain gets longer and the mRNA is read one codon at a time, and the amino acid matching each codon is added to a growing protein chain Detailed: The first methionine- carrying tRNA (methionine is an amino acid specified by the start codon, AUG) starts out in the middle slot of the ribosome,...
Biomarker EEG work - very exciting IPSCs - Prime editing, Base editing, tRNA etc. Based on Ciitizen data! SSB30 Webinar! Check it out on April 15th. https://syngap.fund/ssb Seizure, Sleep & Behavior Ciitizen 103 signed up, 8 are VUS, 95 spots used, 5 TO GO. Sign up now: Ciitizen.com/SYNGAP1 CNF Caregiver survey, due April 23rd. https://syngap.fund/cnf Kids don't get Dx'd, families do. Grandparent article who wants to talk to Barbara? https://syngap.fund/grand Sprint! Bakers dozen 13 groups over $1k! 62K+ https://syngap.fund/sprint Reminders: Enzo 8, Brazil, was our Warrior this week. http://syngap.fund/warriors Also two webinars coming up http://syngap.fund/webinar GI on 4/22 and Advocacy on 5/6. --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message
I discuss ncRNAs (RNA that's ready to perform tasks w/o becoming protein) and then move onto rRNA, tRNA, miRNA, snRNA, and snoRNA. Have fun with all these acronyms lol
We've got special guest Kenobiii in the studio this week to discuss Donald Trump vs. Mexican President Nieto, Chris Brown, the VMAs, Drake thirst and TRNA, AKA Colin Kaepernick. All the shenanigans of Compton Beach, now with double the Compton!
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