Podcasts about rnas

In this episode Dr. Raffaele Teperino shares insights from his ongoing research focused on developmental programming, particularly how paternal health before conception influences not only offspring health but also maternal health outcomes. As we trace his academic journey from studying biotechnology and pharmacology to leading his own lab, Dr. Teperino reflects on his early fascination with medicine, the pivotal experiences that shaped his career, and the integration of epigenetics into understanding metabolic diseases. We discuss the nuances of epigenetics—going beyond simple chromatin biology to examine its wider implications on phenotypic variation. Dr. Teperino emphasizes his approach of modeling relevant physiological phenomena in the lab to better understand the underlying mechanisms driving conditions like obesity and metabolic disruption. A particular focus is placed on his experiences during his postdoctoral years, where he investigated the developmental pathways of hedgehog signaling and its metabolic implications in adipogenesis. Our talk shifts towards the practical implications of his research, highlighting recent investigations into how circadian rhythms and paternal lifestyles influence offspring health. Dr. Teperino reveals his findings on how disturbances in circadian rhythms can lead to intergenerational health issues, showcasing the surprising effects observed in offspring of fathers experiencing circadian misalignment. We delve into the significance of seminal fluid as a potential medium for intergenerational transfer of stress responses, examining the role of stress hormones and their impacts on fetal development. As we explore a fascinating recent study highlighting the impact of paternal diets on future generations, Dr. Teperino underscores the importance of understanding the shorter exposure periods sufficient to trigger these health changes. He presents data that links paternal obesity and preconception health to an increased risk of obesity and insulin resistance in children, challenging traditional narratives around maternal responsibility for offspring health.   References Darr J, Tomar A, Lassi M, Gerlini R, Berti L, Hering A, Scheid F, Hrabě de Angelis M, Witting M, Teperino R. iTAG-RNA Isolates Cell-Specific Transcriptional Responses to Environmental Stimuli and Identifies an RNA-Based Endocrine Axis. Cell Rep. 2020 Mar 3;30(9):3183-3194.e4. doi: 10.1016/j.celrep.2020.02.020. PMID: 32130917. Lassi M, Tomar A, Comas-Armangué G, Vogtmann R, Dijkstra DJ, Corujo D, Gerlini R, Darr J, Scheid F, Rozman J, Aguilar-Pimentel A, Koren O, Buschbeck M, Fuchs H, Marschall S, Gailus-Durner V, Hrabe de Angelis M, Plösch T, Gellhaus A, Teperino R. Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors. Sci Adv. 2021 May 26;7(22):eabg6424. doi: 10.1126/sciadv.abg6424. PMID: 34039610; PMCID: PMC8153725. Tomar A, Gomez-Velazquez M, Gerlini R, Comas-Armangué G, Makharadze L, Kolbe T, Boersma A, Dahlhoff M, Burgstaller JP, Lassi M, Darr J, Toppari J, Virtanen H, Kühnapfel A, Scholz M, Landgraf K, Kiess W, Vogel M, Gailus-Durner V, Fuchs H, Marschall S, Hrabě de Angelis M, Kotaja N, Körner A, Teperino R. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature. 2024 Jun;630(8017):720-727. doi: 10.1038/s41586-024-07472-3. Epub 2024 Jun 5. PMID: 38839949; PMCID: PMC11186758.   Related Episodes The Impact of Paternal Diet on Offspring Metabolism (Upasna Sharma) 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 Mastodon Epigenetics Podcast on Bluesky Dr. Stefan Dillinger on LinkedIn Active Motif on LinkedIn Active Motif on Bluesky Email: podcast@activemotif.com

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.Trump has signaled support for removing the IRA's 'pill penalty', with analysts cautiously optimistic about the executive order. Tariffs are in focus as Q1 earnings get underway, with EU and US pharmas making demands of the European Commission. Former FDA officials warn of potential implications of workforce cuts at the FDA. J&J sets the tariff tone as Q1 earnings begin to roll in. Experts offer advice on optimizing process development and validation steps for cell and gene therapies. In other news, bluebird's second suitor, Ayrmid, fails to make an offer, and the top 6 highest-paid pharma CEOs in 2024 are revealed.The top 6 highest paid pharma CEOs in 2024 have been revealed, with Johnson & Johnson's Joaquin Duato no longer holding the top spot. Duato has urged for a tax fix rather than tariffs to drive US pharma manufacturing. Viking Therapeutics saw a share rally after rival Pfizer discontinued an obesity candidate. Johnson & Johnson's Q1 earnings beat analyst estimates, thanks to Tremfya and Carvykti. Novartis has pledged a $23 billion boost to US operations amid tariff threats. Trump has signaled support for removing IRA's pill penalty and opened a national security probe on pharma imports. The industry is facing uncertainty due to ongoing tariff drama. Trilink's grna for gene editing has been successful, offering high-purity custom guide RNAs for research purposes. Trump's tariff pause sparked a late-day rally for pharma stocks. Some companies, like Glycomine, Merck, and Boehringer Ingelheim, have received significant funding or made deals in the biopharma sector.Senior Editor Annalee Armstrong encourages readers to suggest topics for future coverage in the biopharma industry.

På 90-talet var hon Hollywoods bäst betalda kvinnliga skådespelare. På 00-talet var hon uträknad. Vid 62 års ålder kom hon tillbaka i sitt livs roll. Nya avsnitt från P3 ID hittar du först i Sveriges Radio Play. Med filmer som Ghost, På heder och samvete, Ett oanständigt förslag, och Skamgrepp var Demi Moore ett av filmvärldens största dragplåster under 1990-talet.Men när hon stod på toppen av sina karriär, och krävde lika hög ersättning som sina manliga skådespelarkollegor, blev hon kallad girig. Plötsligt vände allt för Moore, som gick från stekhet till iskall i Hollywood.P3 ID om Demi Moore är berättelsen om uppgång, fall, och återuppståndelse.Efter en tumultartad barndom slog Moore igenom som 19-åring i såpoperan General Hospital. Sprit, knark, vilda fester och snabba nätter på motorcykel genom Los Angeles tog vid. I slutet av 80-talet blev hon och Die Hard-stjärnan Bruce Willis Hollywoods starkast lysande ”power couple”, och därefter tycktes inget kunna hejda Moores klättring till biotoppen.Men knivarna var vässade, redo att stickas in vid minsta felsteg...Över två decennier efter att hennes superstjärnestatus punkterats klev Moore för första gången in i filmvärldens absoluta finrum, när filmen The Substance skapade svallvågor i Cannes. Rollen som den bedagade och ratade Hollywooddrottningen Elisabeth Sparkle låg spöklikt nära Demi Moores egna erfarenheter, och hon hissades till skyarna för sin tolkning.För första gången nämndes Moores namn på allvar i Oscarssammanhang, en halv livstid efter att hon en gång haft den amerikanska filmindustrin i sin hand.Medverkande: Olga Ruin, chefredaktör för filmtidskriften FLM, Anne Thompson, kritiker på sajten Indiewire.Klippen i programmet är hämtade från: ABC News, NPR, CNBC, Red Table Talk, Ljudboksversionen av Moores självbiografi Inside Out, Touchstone Pictures, The Late Shows Youtubekanal, Mubi, AP, Entertainment Tonight, Movieclips

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world. The FDA is facing a potential "catastrophic collapse" due to massive layoffs that are endangering its user fee program, which provides nearly half of its yearly funding. More than half of the senior leadership at the agency has left, leading to a lack of communication, transparency, and human decency. The agency is at risk of losing its funding and ability to support its operations and employee salaries. In other news, Amgen has won an expansion for Uplizna as the first drug for IgG4-related disease, Lilly has made a pact with Sangamo worth a potential $1.4 billion, and Trilink offers custom guide RNAs for CRISPR workflows. The cell and gene therapy sector has seen a 30% investment surge despite market challenges.

Good morning from Pharma and Biotech Daily, the podcast that gives you only what's important to hear in the Pharma and Biotech world.Pharmaceutical companies are pushing back against Trump's tariffs, requesting staggered tariffs as Trump plans for a more aggressive set of tariffs on April 2. Democrats are criticizing Trump's health cuts and policies, with lawsuits being filed and Senator Cory Booker speaking out against the administration. The FDA is facing turnover and layoffs, with concerns about the "revolving door" of talent between the agency and biopharma companies. Denali is making progress in crossing the blood-brain barrier for neuroscience treatments. In the midst of these developments, the biotech industry is seeing growth in cell and gene therapy investments. Despite these challenges, companies like Trilink are offering solutions for accelerating therapy discoveries with custom guide RNAs for CRISPR workflows.In other news, Peter Marks, head of the FDA's Center for Biologics Evaluation and Research, was forced out after clashing with Health and Human Services Secretary Robert F. Kennedy Jr. over transparency issues. Marks, known for his work on innovative therapies like cell and gene therapy, resigned due to the lack of desired truth and transparency from Kennedy. This event has caused turmoil in the biopharma industry, leading to a drop in biotech shares. Additionally, massive layoffs are expanding across HHS as part of Kennedy's plan to remove up to 10,000 staff members. The departure of Marks has raised concerns about the future of the FDA and the industry as a whole. Experts fear that the agency is losing institutional knowledge and experienced leaders, which could have negative implications for drug development and safety. Calls for Kennedy's dismissal have been made by analysts following Marks' resignation. The industry is now facing uncertainty and instability in the wake of these events.

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world.Sanofi and Alnylam have received FDA approval for the first RNAi treatment for hemophilia, with the drug, Qfitlia, indicated for both hemophilia A and B. This approval is significant as it can be given regardless of the presence of neutralizing antibodies against clotting factors VIII or IX. However, the sudden departure of FDA director Peter Marks has caused uncertainty in the biopharma industry. In other news, Vertex has cut a diabetes asset but analysts remain optimistic about their phase III option. Lilly's RNA silencer has shown promising results in lowering a key cardiovascular biomarker. Trilink is offering custom guide RNAs for CRISPR workflow to accelerate therapy discoveries. Despite market challenges, the cell and gene therapy sector has seen a 30% investment surge. Companies like Amgen, Aldeyra, and Argenx are among those with upcoming FDA actions. Arbutus has announced layoffs, while big pharmas are pushing boundaries in radiopharmaceuticals. Michelle Werner of AltoRNA is focused on making better drugs. Safety questions are looming in Duchenne as Dyne and Wave plan FDA filings. There are job opportunities available in data management and program leadership within the biopharma industry.Moving on to other news, several big pharmaceutical companies such as Novartis, Bayer, AstraZeneca, Bristol Myers Squibb, and Eli Lilly are competing in the radiopharmaceuticals market, which is projected to be worth over $13 billion by 2033. The FDA is expected to announce decisions on therapies for dry eye disease soon. Michelle Werner, CEO of AllTrna, is focused on developing trna-based treatments for various diseases.Safety concerns are emerging in the Duchenne muscular dystrophy space as companies like Dyne and Wave plan FDA filings. The EU rejected Lilly's Alzheimer's drug Kisunla, Biontech's bispecific showed promise in treating SCLC patients, and Wave's duchenne exon-skipper reversed muscle damage in a mid-stage trial. Job opportunities within the biopharma industry were also highlighted for those interested.Thank you for tuning in to Pharma and Biotech daily - keeping you updated on all the latest news in the world of pharmaceuticals and biotechnology.

In this episode of clinical conversations, Dr Kat Ralston chats with consultant toxicologist Dr Emma Morrison about poisoning in the older adult. They explore why we need to think differently about deliberate self-harm in the older adult and talk through common toxicology cases, including decision-making around escalation. Finally, they consider a common sense approach to what we can do differently as clinicians to reduce the risk of self-harm and suicide in this patient group. Dr Morrison trained in medicine at the University of Glasgow, with an intercalated BSc in Physiology. She also completed a PhD investigating to role of short RNAs as biomarkers and mediators in toxic injury. In 2020, Emma become a Consultant Physician at the Royal Infirmary of Edinburgh. Emma's NHS work continues to support her passion of ensuring transparent and equitable decision making in prescribing, supporting the central tenets of value-based medicine. Her roles within medicines governance include Chairing Lothian's Area Drug and Therapeutics Committee and is a committee member of the SMC. Dr Kat Ralston is a geriatric medicine registrar in Edinburgh. She is also the Education Co-Vice Chair and the joint Podcast Lead for the RCPE Trainee & Members' Committee (T&MC). --Useful Link-- TOXBASE - https://www.toxbase.org/ Recording date: 19 December 2024 -- Follow us -- https://www.instagram.com/rcpedintrainees https://twitter.com/RCPEdinTrainees -- Upcoming RCPE events -- https://www.rcpe.ac.uk/events -- Become an RCPE Member -- https://www.rcpe.ac.uk/membership/join-college Feedback: cme@rcpe.ac.uk

In this episode of Careers in Discovery, Tom sits down with Dominique Verhelle, Co-Founder, President and CEO of NextRNA Therapeutics, a company pioneering the use of long non-coding RNAs in drug discovery. Dominique takes us through her unconventional journey - from aspiring flight attendant to Biotech entrepreneur - sharing the pivotal moments that shaped her career. She talks about the challenges of leading a startup through uncertainty, balancing science and business as both CSO and CEO, and why strategic timing is key in career growth. We also discuss the evolution of the dark genome field, NextRNA's recent partnership with Bayer, and what's next for this exciting company as it moves towards the clinic. A fascinating conversation on leadership, resilience, and pushing the boundaries of biology.  

In this episode of Daily Value, we look at how paternal alcohol consumption before conception could influence offspring health, longevity, and even accelerate aging. Referencing studies from Andrology (PMID: 38044754) and Aging and Disease (PMID: 39122451), we examine how sperm RNA modifications and mitochondrial dysfunction may persist long after alcohol cessation—potentially programming offspring for metabolic disorders, reduced NAD+ levels, and faster cellular aging.Discussion Points:Sperm Epigenetics: what rodent data tells us baout alcohol exposure altering small RNAs in sperm, disrupting gene regulation in the developing embryo.Mitochondrial Dysfunction: newer rodent data showing lower SIRT1/SIRT3 levels, and lower NAD+ in offspring whose parents were exposed to alcohol.Practical Takeaways: How long should alcohol cessation be before conception could help restore sperm quality and reduce the risk of accelerated aging in children for people who drink regularly.https://pubmed.ncbi.nlm.nih.gov/39122451/ https://pubmed.ncbi.nlm.nih.gov/38044754/ Support the show

Os MicroRNAs são pequenas moléculas de RNAs, que regulam a produção de proteínas das nossas células. Eles têm entre 17 e 25 nucleotídeos e reconhecem RNAs mensageiros-alvos, por meio da complementariedade entre as sequências. Se você quer entender um pouco mais sobre estes novos RNAs, que conquistaram o Prêmio Nobel de Fisiologia e Medicina em 2024, e saber o impacto que estas novas tecnologias terão na nossa vida, este episódio é para você. Então Vem Cienciar conosco!

In this episode of Genetics in Your World, Early Career Scientist Multimedia Subcommittee member Tammy Lee has a conversation with Dr. Jordan Brown, a recent alumnus from the University of Chicago, about factors involved in gene silencing mediated by small RNAs. Read Dr. Brown's paper titled, “Sensitized piRNA reporter identifies multiple RNA processing factors involved in piRNA-mediated gene silencing,” published in the August 2023 issue of GENETICS: ​​https://doi.org/10.1093/genetics/iyad095. Music: Loopster Kevin MacLeod (incompetech.com). Licensed under Creative Commons: By Attribution 3.0 License, http://creativecommons.org/licenses/by/3.0/ Hosted on Acast. See acast.com/privacy for more information.

The Nobel Prize as Evidence of Intelligent Design What does this year's Nobel Prize have to do with intelligent design? A lot more than you may imagine! On this episode I've invited Dr. Fazale Rana from Reasons to Believe and Dr. Casey Luskin from the Discovery Institute to review and discuss the Nobel Prize-winning discovery of micro-RNAs and how it supports intelligent design and weakens the evolutionary paradigm. Join us as we dive into a fascinating discussion on the mechanisms of life.

On today's episode of The Wholesome Fertility Podcast, I speak to Dr. Jeff Gross, a top Neurosurgeon who has a background specializing in athletic injuries and spine procedures. Dr. Jeff shares his journey from spinal neurosurgery to the forefront of regenerative medicine, focusing on the transformative potential of stem cells and exosomes. He explains the science behind stem cells, their applications in treating joint degeneration, and their role in anti-aging and fertility. Dr. Jeff also discusses the regulatory landscape, the cost of treatments, and the exciting future of stem cell research, including innovative approaches to enhance mitochondrial function which has a lot of promise when it comes to egg and sperm health.   Takeaways   Stem cells can be used to treat various conditions, including inflammation. Accumulation of inflammation is a key factor in aging and conception challenges. Exosomes may play a significant role in the benefits of stem cell therapy. Regenerative medicine is evolving rapidly, with new research emerging. The cost of stem cell treatments can vary but is becoming more accessible. Stem cells are sourced from well-regulated donor programs in the US. Direct injection of stem cells may yield higher doses than IV administration. Future research may explore the use of exosomes in fertility treatments. Dr. Jeff emphasizes the importance of personalized treatment plans.      Guest Bio:   Dr. Jeffrey Gross graduated from the University of California, Berkeley with a degree in biochemistry and molecular cell biology. He earned his Doctor of Medicine in 1992 from the George Washington University School of Medicine. He contributed to virology research during his studies. After graduating, he undertook a residency in neurological surgery at the University of California, Irvine Medical Center until 1997. He then pursued a Fellowship and Chief Residency in Spinal Biomechanics at the University of New Mexico until 1999. Licensed in California and Nevada, Dr. Gross has SPINE practices in Orange County and Henderson, Nevada. A trained neurological surgeon, he specializes in athletic injuries and spine procedures, and offers longevity and biohacking consultations. He achieved board certification by the American Board of Neurological Surgery and is a member of several prestigious medical societies. He has written textbooks and articles in his area of expertise and is a peer-reviewer for the state of California and a scientific journal. Since 2020, Top Doctor recognized Dr. Gross as a leading Neurological Surgeon. He also received HealthTap's 2022 Top Doctor Award as a top Neurological Surgeon in the U.S. Dr. Gross founded ReCELLebrate, focusing on anti-aging and regenerative medicine. The mission for ReCELLebrate emphasizes offering modern biochemical treatments and considering surgery as a last resort.     Websites: https://recellebrate.com/ https://www.instagram.com/recellebrate/ https://www.tiktok.com/@recellebrate https://www.youtube.com/@stemcellwhisperer https://www.linkedin.com/in/jeffrey-gross-md-5605605/       For more information about Michelle, visit: www.michelleoravitz.com   The Wholesome FertilityFacebook group is where you can find free resources and support: https://www.facebook.com/groups/2149554308396504/ Check out Michelle's Latest Book: The Way of Fertility! https://www.michelleoravitz.com/thewayoffertility Instagram: @thewholesomelotusfertility   Facebook: https://www.facebook.com/thewholesomelotus/     Transcript:   Michelle (00:00) Welcome to the podcast, Dr. Jeff.   Dr. Jeff (00:03) Thank you so much for having me. Nice to see you.   Michelle (00:06) Nice to see you as well. So you definitely have a very long, impressive background. So I'd love for you to share your story on how you got to really to the anti-aging stem cells work that you do, So I'd love to just get a quick background so the listeners can hear.   Dr. Jeff (00:26) Sure, thank you for that. It was by accident of sorts, maybe directed accident because I was practicing as a spinal neurosurgeon, taking care mainly of neck and back trouble, some other neurological issues, nerve problems, things like that. But my practice was highly consultative, a lot of opinions, second opinions. I was seeing patients who had neck and back problems that were perhaps...   mistreated or not fully treated elsewhere. And I was kind of, I was kind of a catchall for that. But my patients came to me one at a time. And these are patients that had tried different things and they just didn't work adequately. Like physical therapy, like anti-inflammatories, like rest, like, you know, chiropractic, acupuncture, maybe spinal epidural injections or things like that.   And they'd come in and say, well, you know, help for a minute, but just wasn't enough. I'm still having a lot of trouble with my neck or back or pinch nerve or whatever. And I say, well, the next thing on the menu is to talk about surgical options. And they'd say, well, I'm not that bad. So wait a minute. Okay, good. Cause I was hoping you would say you're not ready for that. Cause I really didn't want to offer that to you. Cause I've always been on the slow to operate side of things. So, a lot of them would say, well, how about lasers or how about.   Michelle (01:37) Mm-hmm, yeah.   Dr. Jeff (01:52) herbs or how about cannabis or how about stem cells? And I heard the stem cell one more than once and chance favors the prepared mind. So my undergraduate background is in molecular cell biology, which is kind of the stem cell, know, root of stem cell biology. And, you know, when you get whisked off from undergraduate to med school and residency and practice,   you don't really get to apply that cool science. So the nerd part of me took over and said, I wonder what's happened in all these years since I went to undergraduate, you know? So instead of going to the Stodgy Neurosurgeon Convention every year, or more than one, where the same people pat themselves on the back for saying the same things for decades, I decided I'm going to open my mind and start going to stem cell and regenerative medicine meetings.   Michelle (02:46) Mm-hmm.   Dr. Jeff (02:46) So I can offer this to my spine patients. So I did that and I not only brought back a new tool to offer them, but it blossomed into so much more. You can't get access to regenerative medicine, stem cell medicine, and I'm using those phrases sort of interchangeably here, and not say, I'll help your knee or your ankle or your shoulder or your...   autoimmune issues or other hyper inflamed states. Or, you you read more and you see accumulation of inflammation is really the aging process. And if you can fight against inflammation accumulating, you're fighting against aging. So the whole anti-aging umbrella opened up and here I am, you know, six years later where spinal medicine is only a small percentage of my practice and I love it.   Michelle (03:33) Mm-hmm. Yeah.   That's great. So, so for people listening, some people might be like, okay, I kind of heard about stem cells, but what exactly are they? So just for people listening for the first time, we're really not understanding that aspect of like what they are. Cause we hear about it a lot. And over the years, like you said, stem cell research has really drastically changed and has gone into so many different things. Sometimes we hear about like   Dr. Jeff (03:45) So.   Yeah.   Michelle (04:12) you know, back in the day about them growing a liver, like, you know, the possibility of growing organs through stem cells. for people who are really new to this, I would love for you to break it down.   Dr. Jeff (04:15) Yeah. Yeah. Yeah.   sure, let's do stem cell 101. That's great. and being a fertility podcast, this is relevant probably more than any other area of medicine because fertility and creating an embryo is, you know, creating a group of stem cells that divide and grow into a fetus who's made of all stem cells, right? And then,   Michelle (04:28) Hahaha   Right.   Dr. Jeff (04:54) then that fetus is born and it's a baby and the baby grows for 18, 20, 25 years, whatever. And that growth requires stem cells. And then after that, an adult has to maintain, has to replace, has to restore, has to regenerate and that requires stem cells. So what are these? They are cells from which other cells arise, from which other cells stem from. Okay? So, and they are...   Michelle (05:20) Mm.   Dr. Jeff (05:24) They are powerful because there are different types, right? We throw out the phrase stem cells, but when you're a one cell or a two cell or a four cell embryo, you have these omnipotent cells. They can form any part of your body. They are amazingly powerful. As those divide and differentiate, meaning take on some specific characteristics, they become less powerful and more directed, and those are called pluripotent.   And a pluripotent might be able to regrow a limb. And as you, as you, and many of your listeners probably know, there are certain species that can still do that. Like a starfish, you cut off a leg of a starfish, it can regrow it. Or a tail of a lizard or a limb of an axolotl, which is a strain iguana like creature from Mexico. So there are many examples in biology where these pluripotent stem cells can be called upon. And you mentioned maybe regrowing a liver someday.   that will probably require some knowledge of pluripotent stem cells, which are being looked at. However, after these stem cells sort of retain, we bank them in our body as adults, those are called multipotent. So they can't regrow a limb, they can't regrow an organ per se, although they can replace some organ cells and regenerate. And you were always replacing cells, we're replacing skin cells and   you know, hair follicles and all kinds of things that require stem cells. If you have an injury and you cut yourself, you, require stem cells to help come repair that. and you know, we make new blood cells all the time that requires stem cells in our bone marrow. So we are using our stem cells. This is not new. We just know more about it now. And the whole move in regenerative medicine is, is to take   Michelle (07:03) Mm.   Dr. Jeff (07:19) a lesson from that biology and use it strategically to help somebody do something they need.   Michelle (07:27) So interesting. So give us a couple of examples on how it works in the body. Like for somebody who needs it, for example, whereas like a therapy.   Dr. Jeff (07:34) Well, the-   Right. So the low hanging fruit as an example, are joint degeneration. Also called arthritis or osteoarthritis vaguely, or some people it's called bone on bone if it's bad enough. Right. And these are your painful joints. It could be from an old injury, an old arthroscopic surgery. It could be from just, you know, accumulated wear and tear. And this is a problem with the joints where the cartilage   is, you know, down and the joint is painful. You can't use it as well stiffness, et cetera. And it slows people down. And when you slow people down, particularly in their older years, they're less mobile and then they can't maintain their bones, their bone density, AKA, you know, the one way to fight osteoporosis is weight bearing exercise. So if you can't, if your joints hurt, you're not going to do it. And muscle mass, cause both bone density and muscle mass are correlated with longevity. So if you keep moving.   You maintain your muscles and bones, you'll live longer statistically. So in any event, we want to preserve joints. And that's kind of why I got into this field. I'm a structural guy of the spine and it easily extrapolates to the other joints. And most of the research, the well-published research comes from knees and other joints. And just parenthetically, most of the good published research that we follow, because we're not just shooting from the hip here.   We do shoot some hips, but it comes from Asia and Europe. The United States is behind, although we can do these things. And, you know, we can talk about that later, but the short of it is we have a really good track record of helping people with degenerated joints in reducing pain and improving function. And we do have some examples with where we've done some MRIs.   Michelle (09:09) Ha ha ha!   Dr. Jeff (09:37) before and after and the after MRIs have shown some regrowth of like knee cartilage, for example, and things like that. you know, we're not allowed to make any claims because we're not yet approved for marketing claims, but I can show examples and I have to say like you invest in stocks, know, past performance does not guarantee future results or something like that, but in medicine, never, yeah, yeah.   Michelle (10:01) Right, and each person is different and unique. Yeah.   Dr. Jeff (10:05) But anyway, it's better, listen, if you want to try to avoid a joint replacement surgery, it's worth looking into. So whether it's spine or joints, so that's the easy stuff. Low hanging fruit, I call it. The other stuff is anything with an inflammatory problem in your body can potentially have benefits from regenerative medicine on its face being a natural anti-inflammatory. So for example, autoimmune problems with hyperinflammation.   You know, like rheumatoid arthritis, thyroiditis, inflammatory bowel syndromes, MS, things that have an inflammatory component. Also, most diseases of aging are diseases of inflammation. So coronary artery disease, Alzheimer's, things like this, all have an inflammatory component. And this allows me to overlap into your area is there are some causes of fertility.   issues that have an inflammatory component, whether it's a uterine issue or ovarian failure. And sometimes fighting that inflammation, whether it's through lifestyle changes, diet, exercise, mindfulness, sleep, reducing mental stress, all those things can help reduce the inflammation and help potentially lead to successful pregnancy. The same can go for use of   regenerative biologics like stem cells, and they're not the only thing we use. And there are wonderful publications. And before we got on this, I refreshed my knowledge by doing a little homework. And there are even newer publications on use of these things to improve fertility. Now, most of these are from China because they are way ahead of us. But that doesn't mean they can't be applied here outside of China.   Michelle (12:01) Interesting. So interesting. So how do they get these stem cells?   Dr. Jeff (12:07) So stem cells and other related biologic material in the US comes from a well-regulated donor program. Typically the donors are women who are planning to have a C-section. Some of the labs even recruit the donors in the first trimester, make sure they're having a healthy pregnancy, they're not using substances they shouldn't be using, they take their prenatal vitamins, they're not in any high-risk behaviors.   And at the time of the C-section, they simply, and once the mother is congratulated with her new baby, they take the amniotic fluid, they take the umbilical cord, they take the placenta and they put them on ice in a sterile fashion and they go to an FDA compliant certified lab that can test and screen the materials, make sure there's nothing in there, no diseases, no problems, and then make it available to clinics and end users like myself.   So there are myths that all kinds of crazy stuff are happening out there, but not here in the US. We use highly regulated donor processes.   Michelle (13:19) When you have the stem cells from donors, can they be multiplied or is it just like a finite amount? Whatever is there is there.   Dr. Jeff (13:28) They can be, there are labs that put them in culture, would let them grow and divide and that's one thing that can be done. Now, just like anything, a copy of a copy of a copy tends to lose its vitality. So, things like telomere length, which is an aging marker, that changes with each division of a cell. So I don't like to use a divided material.   Michelle (13:50) Mm-hmm.   Dr. Jeff (13:58) I use just fresh first pass stuff. Maybe your listeners are a little young for this, but there's a really funny movie called Multiplicity, where Michael Keaton clones himself, and each clone is a little bit wonkier than the original. if you want a good laugh, yeah, check out that movie. But in short, I prefer the actual native original self.   Michelle (14:15) Comedy used to be so much better.   Right. Got it. Is this similar to cord blood, you know, when they, when the baby's born and they say, do you, you know, you can opt to do that and then store   Dr. Jeff (14:27) When we do self,   Yeah, let's tap into that for just a second and unpack it if it's okay. know, historically you would be offered to donate or not donate, but store your umbilical cord. And the purpose of that was, God forbid your child gets leukemia in seven years, you have a matched set of cells that they culture, they do divide.   Michelle (15:01) Mm-hmm. Right.   Dr. Jeff (15:02) and replace the child's bone marrow, you don't have to worry about a donor or a match. Now you can do that and you can also use, in some labs we'll use those umbilical cord cells as a source for any other future purpose, whether it's a joint problem or what have you, they're now doing that. In fact, you can use that for family members as well. So the reasons for a bank in your umbilical cord, and they probably won't tell you in the pamphlet, because it's not yet approved for marketing claims.   Michelle (15:19) Mm-hmm.   Mm-hmm.   Dr. Jeff (15:31) is much more than just, you know, just in case there's a case of leukemia, you need a full bone marrow replacement.   Michelle (15:39) So interesting. how, when you do have the stem cells, first of all, it must cost a fortune, it sounds like, it's limited. It's not something that you, because you're depending on donors.   Dr. Jeff (15:52) No, well, there's a little bit more to it. And that, and I keep using the phrase stem cells and other biologics. Let's, let's talk about other biologics for a minute because some of these other biologics are less expensive and here in the U S it's, it's affordable. You don't have to necessarily leave the country and go to go to central America or, you know, Hong Kong to get this or Europe. A lot of the professional athletes historically went to Europe, but they're, they're getting it here, here in the U S too.   Michelle (15:59) Okay.   Mm-hmm.   that's good.   Dr. Jeff (16:22) But we found out that if we gave you stem cells, let's say you came over and I hooked up an IV and we gave you stem cells, in 10 to 14 days, those would be out of your system. However, the benefits would go on for weeks or months or even some of the benefits would be prolonged. So why is that? If the stem cells are gone, what's going on? Well, it turns out the stem cells aren't really doing all the work. The stem cells are delivering cell to cell communicating and influential   Michelle (16:31) Mm-hmm.   Dr. Jeff (16:52) biomolecules, peptides, growth factors, small RNAs from cell, from the stem cells to your cells, reinvigorating and activating your cells to do that work. And those, those communication packets are called extracellular vesicles or for short exosomes. And you may have seen this, a lot of estheticians use them. You know, they can do the atom to your microneedle facial.   Michelle (17:11) Mm-hmm. Mm-hmm.   Mm-hmm.   Dr. Jeff (17:20) It's sort of an advanced vampire facial with these exosomes. So the exosomes are probably doing most of the work that the stem cells were doing. And there are advantages. They penetrate tissue better. They're easier to store and handle. They'll cross the blood brain barrier if you want them in your brain and nervous system. And they're less than half the price of stem cells. So we can do things that used to cost, you know, 20, $30,000 out of this country.   for less than half of that here, because the big cost is the materials, these biologics. So what does it cost was your original question, but now that you know we're using these exosomes preferentially in a lot of these cases. And by the way, as an aside, all stem cells, sorry, start over, all cells make exosomes. We're using stem cell derived exosomes from amniotic fluid, which is quite abundant. So there are really no cells in this.   Michelle (18:11) Mm-hmm.   Mm-hmm.   Dr. Jeff (18:19) There's no matching that needs to be done. and it's, it's wonderful. So, the, you know, for example, treating a knee, if we're trying to repair a knee, help someone heal a knee, we're asking their cells to do the work. We're just providing the, the, the re-instruction to tap back into the original factory that made that joint in the first place. And something that like that is kind of two doses of biologics, one above one below the knee.   the injection, the facility and everything where we do it as sterile. All that is, you know, in the nine to 12,000, depending on what we're doing. So it's not, it's not crazy. And IVs, if we do an IV, that's anywhere from like 4,000 to 8,500, depending on the dose.   Michelle (18:54) Mm-hmm.   And how many times would somebody have to do that?   Dr. Jeff (19:07) Maybe once. Usually the joints are one and done and then they go back to their normal wear and tear. So is it possible someone's going to come back in in 20 years and need it again maybe, but that's okay. We follow a French protocol that has published 15 year follow-up and we follow that protocol how they do it. And they've had over 82 % of the patients had wonderful results at the 15 year mark. We're waiting for them to publish the 20 year mark.   Michelle (19:10) Mm-hmm.   Mm-hmm.   Dr. Jeff (19:35) So we're not making this up. We're just duplicating what's already been done and good science that's out there.   Michelle (19:42) And for inflammatory conditions, autoimmune conditions, or even fertility, well, you know, because it's secondary to that a lot of times. Do you use IV? So really get it right into the bloodstream. Okay.   Dr. Jeff (19:51) Right, right.   Yeah, I would definitely. yeah. Yeah. And that's how we approach anti-aging anyway. People are biohackers, anti-agers that come in. This is what we do. And we, we do an IV. We, we try to figure out a dose that makes sense for that person based on the budget and their age and maybe their inflammatory markers and their blood tests and other things. And then we see how long it lasts. And some people get a year, two years. Some people get, you know, six months.   Some people come in preventively and do every three months a lower dose. just, we customize it for the individual.   Michelle (20:33) And that crosses the blood brain barrier. So it's good for brain health, really for just everything. The system.   Dr. Jeff (20:37) Yeah. Anywhere there's an inflammatory burden, we'll do it. But exosomes do cross the blood-brain barrier. And let me go off script here for a second. For listeners that have been pregnant before, in later trimesters, a pregnant woman has glowing skin and her hair is growing wonderfully. And typically, there's not a lot of joint pain, maybe   Michelle (20:43) Mm-hmm.   Dr. Jeff (21:06) low back pain from carrying the weight, why is that woman in, you know, not having this great skin and all that, it's because that woman is getting a daily dose of stem cell derived exosomes because they also not only cross the blood brain barrier, they cross the placental barrier. So what we do is almost simulate that in a single dose.   Michelle (21:25) Mm-hmm. Got it.   That's so interesting. in that case, when you are doing IV, is that also one and done?   Dr. Jeff (21:37) No, like I was saying, it depends on what benefits someone gets and for how long they last. It could be depending on the person's need. Now, if it's someone who's got an inflammatory problem and they're just trying to get pregnant, could be a one and done. If it's someone that has benefited from it and wants to do it repetitively, then we would help support that and make it available.   Michelle (21:43) I see.   Mm-hmm. Done.   Have you heard of this being used and injected directly into like uterus or those areas or is it typically more like IV?   Dr. Jeff (22:11) So not into the uterus, although there are examples in men of injecting the testes where they're not producing adequate sperm counts. I think IV would be a first. So I didn't read anything about ovarian injection yet. Could that be coming? Possibly. IV is obviously an easier thing to do. So I would try the IV first. But you're right, you're going to get a higher dose if you inject directly.   Michelle (22:20) Mm-hmm.   Or ovaries maybe?   Mm-hmm.   Dr. Jeff (22:40) That might be something to look at. haven't done it. We do have some sexual health shots we do at the exosomes now where we do P shots and O shots for men and women respectively for improvement in sensation, lubrication, that kind of.   Michelle (22:53) Mm-hmm.   I know that they do PRP with the ovaries and I think also uterus. So that's why I was asking because it's kind of similar, you doesn't have the same exact substance, but it's the idea of stimulating.   Dr. Jeff (23:14) No, I completely agree with that. PRP is basically a very lower, it's the lowest end self-donated regenerative medicine. And it probably contains some cells and some exosomes in there.   Michelle (23:21) Mm-hmm. Right.   So interesting. that's really fascinating. for you specifically, like if people wanted to work with you, do they have to come visit you, your office, where you are?   Dr. Jeff (23:38) Not necessarily. So, you know, most of what we do, we start out remotely. The vast majority of my patients come from somewhere other than Las Vegas, where I'm located, actually Henderson, Nevada, which is a suburb of Las Vegas. Most people start remotely. We do a lot of the blood tests or if they need MRIs or what have you remotely, and we only invite them to come to town if there's a reason to come to town. We do have some other colleagues in other parts of the states too that can do IVs.   things like that so we can sometimes refer. Yeah.   Michelle (24:09) Mm-hmm. It's really fascinating. It seems like state of the art. It's like the new thing that's coming out.   Dr. Jeff (24:13) and   It's a, and there are things coming. if you'll allow me to just jump there for a second. you know, we are working on some projects here at, at my practice. one of them involves exosomes that are stuffed with extra mitochondria. And for those of you that don't know, that's a small part within the cell. It's kind of a cell within the cell. we learned in high school biology, it was the powerhouse of the cell. made the energy, but it actually does much more.   Michelle (24:22) of course. Yeah.   Hmm   Dr. Jeff (24:46) And some causes of infertility relate to poor mitochondrial activity in the cells of the ovaries and things like that. So we're looking at exosomes that could be overstuffed with, that can donate more mitochondria. So that could be very useful. There are many other reasons to do that as well. And then we're even involved in a project that may be useful to help patients with cancer. And this is a particular exosome.   that comes from a certain type of immune cell, a T cell in our body, whose job is to identify, circulate around the body, identify, and then selectively remove or kill an abnormal cell like a cancer cell. So imagine that as an augmentative therapy or even as a preventative. Yeah, so we're hot on that trail. That's coming soon to a, to a re-celebrate clinic near you.   Michelle (25:36) That's fantastic.   I love that. That's awesome. That's really amazing. And what have you seen so far in regards to fertility? you seen people do this treatment and it work? with fertility, there's so many different reasons for why. I mean, it could be so many different. It's really a range of underlying conditions, but what have you noticed so far?   Dr. Jeff (26:03) Correct. So honestly, I don't have a fertility practice that's pretty far afield from what I do. I do a lot of structural work, a lot of joints, a lot of spine. We do some autoimmune and a few other things. But I have talked to colleagues, fertility specialists in the past, and we've talked about exosomes. I was at a biohacking conference in Texas last year.   Michelle (26:11) Yeah.   Dr. Jeff (26:32) the Dave Asprey event and someone came up to me and asked me about fertility. So I know it's on my radar. It's just not something we put out there necessarily. had one gentleman that had low sperm count. We had talked about doing something for him, but he didn't do it yet.   Michelle (26:34) Mm-hmm.   But have you seen or through colleagues or any studies that have shown even just IV, doing this with IV that it's helped?   Dr. Jeff (27:00) I've only read the abstract of some of the Chinese studies because we don't always get the full article translated. But most of those studies speak to direct injection. They have a lot of animal studies. So I don't have information on the clinical use of...   Michelle (27:07) Okay.   Dr. Jeff (27:25) exosomes personally for fertility, but I know that others have talked to me about it. So it's being done. And I, I did look it up online before we met today and you can actually find, there was a clinic in Europe that was advertising it for this purpose for fertility. Yeah.   Michelle (27:31) Mm-hmm.   Interesting. Yeah, which I'm sure people don't really have to go all the way to Europe. I'm sure also if you get the IV and your body's going through this anti-aging and your mitochondria are benefiting and also, which is very much linked to aging eggs. So you want to like revitalize and reawaken and also lower inflammation that also helps with egg quality and sperm quality.   Dr. Jeff (27:54) and   Michelle (28:08) So this is just definitely something that I found when I saw you, I was like, this is really interesting. I think that it's something that people should be hearing about. And I'm sure I wouldn't be surprised if in the future, a lot of fertility clinics are going to start looking into this as well.   Dr. Jeff (28:26) Yeah, no, the one that was advertising is an international fertility group, I think, in Eastern Europe. And they specifically have a webpage on this. Now, we can't have those webpages here in the US because we are not yet approved for marketing claims.   Michelle (28:32) Mm-hmm.   Mm-hmm. Right.   It's so interesting how all that works. But yeah, this is great. This is a really interesting topic and really great information. I love like cutting edge stuff. I love that it's kind of like to be continued because you're still like, You already have learned so much, but of course, there's so much more coming, which is exciting. I find it really exciting.   Dr. Jeff (29:00) Yeah.   I do too. have this renewed interest. know, I'm, I'm a self admitted nerd. So this is, gets me back into things that are very exciting. I don't get to do the same thing day after day anymore. that's, that's.   Michelle (29:19) I love that.   Yeah, for sure. So awesome. So for people who want to learn more about you and what you do, how can they find you?   Dr. Jeff (29:30) Check out Re-Celebrate because you're celebrating the renewal of your cells. That's spelled R-E-C-E-L-L-E-B-R-A-T-E. And that is our website is recelebrate.com. Instagram is recelebrate at recelebrate it. LinkedIn, Pinterest, YouTube, but just type in recelebrate, you'll find it.   Michelle (29:52) Awesome. And you'll find it also in the episode notes. So I'll share all the links in there, as well as information about Dr. Jeff. So this is a great conversation. This is really, really great. And I appreciate you coming on and explaining it so nicely and really breaking it down for us, you know, people that don't have that background. So thank you so much for coming on today, Dr. Jeff.   Dr. Jeff (30:03) Yeah.   you   It's been my pleasure, thank you for having me.

المصادر The Catalyst: RNA and the Quest to Unlock Life's Deepest Secrets By Cech, Thomas R. https://www.researchgate.net/figure/Human-cornea-structure-and-composition-A-Human-cornea-anatomy-B-The-human-cornea_fig1_379012868 https://www.genome.gov/genetics-glossary/Messenger-RNA-mRNA https://www.genome.gov/genetics-glossary/Transfer-RNA-tRNA https://www.genome.gov/genetics-glossary/Ribosome https://en.wikipedia.org/wiki/Ribozyme https://en.wikipedia.org/wiki/List_of_RNAs https://www.salk.edu/news-release/modeling-the-origins-of-life-new-evidence-for-an-rna-world/ https://www.thoughtco.com/dna-versus-rna-608191 https://math.mit.edu/classes/18.417/index.html https://www.genome.gov/genetics-glossary/Nucleolus https://www.sciencefacts.net/rna-polymerase.html https://www.vedantu.com/biology/start-codons-in-dna-and-rna https://www.slideshare.net/slideshow/structure-and-function-of-messenger-rna-mrna/56603656 https://www.genome.gov/genetics-glossary/Intron https://rsscience.com/ribosomes/ https://earth.callutheran.edu/Academic_Programs/Departments/BioDev/omm/jsmolnew/trna/trna.html https://www.nist.gov/image/rnagraphics-introv2-01png https://en.wikipedia.org/wiki/Hammerhead_ribozyme

Support the show to get full episodes and join the Discord community. The Transmitter is an online publication that aims to deliver useful information, insights and tools to build bridges across neuroscience and advance research. Visit thetransmitter.org to explore the latest neuroscience news and perspectives, written by journalists and scientists. Read more about our partnership: https://www.thetransmitter.org/partners/ Sign up for the “Brain Inspired” email alerts to be notified every time a new “Brain Inspired” episode is released: https://www.thetransmitter.org/newsletters/ To explore more neuroscience news and perspectives, visit thetransmitter.org. Hessam Akhlaghpour is a postdoctoral researcher at Rockefeller University in the Maimon lab. His experimental work is in fly neuroscience mostly studying spatial memories in fruit flies. However, we are going to be talking about a different (although somewhat related) side of his postdoctoral research. This aspect of his work involves theoretical explorations of molecular computation, which are deeply inspired by Randy Gallistel and Adam King's book Memory and the Computational Brain. Randy has been on the podcast before to discuss his ideas that memory needs to be stored in something more stable than the synapses between neurons, and how that something could be genetic material like RNA. When Hessam read this book, he was re-inspired to think of the brain the way he used to think of it before experimental neuroscience challenged his views. It re-inspired him to think of the brain as a computational system. But it also led to what we discuss today, the idea that RNA has the capacity for universal computation, and Hessam's development of how that might happen. So we discuss that background and story, why universal computation has been discovered in organisms yet since surely evolution has stumbled upon it, and how RNA might and combinatory logic could implement universal computation in nature. Hessam's website. Maimon Lab. Twitter: @theHessam. Related papers An RNA-based theory of natural universal computation. The molecular memory code and synaptic plasticity: a synthesis. Lifelong persistence of nuclear RNAs in the mouse brain. Cris Moore's conjecture #5 in this 1998 paper. (The Gallistel book): Memory and the Computational Brain: Why Cognitive Science Will Transform Neuroscience. Related episodes BI 126 Randy Gallistel: Where Is the Engram? BI 172 David Glanzman: Memory All The Way Down Read the transcript. 0:00 - Intro 4:44 - Hessam's background 11:50 - Randy Gallistel's book 14:43 - Information in the brain 17:51 - Hessam's turn to universal computation 35:30 - AI and universal computation 40:09 - Universal computation to solve intelligence 44:22 - Connecting sub and super molecular 50:10 - Junk DNA 56:42 - Genetic material for coding 1:06:37 - RNA and combinatory logic 1:35:14 - Outlook 1:42:11 - Reflecting on the molecular world

When I think of digital biology, I think of Patrick Hsu—he's the prototype, a rarified talent in both life and computer science, who recently led the team that discovered bridge RNAs, what may be considered CRISPR 3.0 for genome editing, and is building new generative A.I. models for life science. You might call them LLLMs-large language of life models. He is Co-Founder and a Core Investigator of the Arc Institute and Assistant Professor of Bioengineering and Deb Faculty Fellow at the University of California, Berkeley.Above is a brief snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Here's the transcript with links to the audio and external links to relevant papers and things we discussed.Eric Topol (00:06):Well hello, it's Eric Topol with Ground Truths and I'm really delighted to have with me today Patrick Hsu. Patrick is a co-founder and core investigator at the Arc Institute and he is also on the faculty at the University of California Berkeley. And he has been lighting things up in the world of genome editing and AI and we have a lot to talk about. So welcome, Patrick.Patrick Hsu (00:29):Thanks so much. I'm looking forward to it. Appreciate you having me on, Eric.The Arc InstituteEric Topol (00:33):Well, the first thing I'd like to get into, because you're into so many important things, but one that stands out of course is this Arc Institute with Patrick Collison who I guess if you can tell us a bit about how you two young guys got to meet and developed something that's really quite unique that I think brings together investigators at Stanford, UCSF, and Berkeley. Is that right? So maybe you can give us the skinny about you and Patrick and how all this got going.Patrick Hsu (01:05):Yeah, sure. That sounds great. So we started Arc with Patrick C and with Silvana Konermann, a longtime colleague and chemistry faculty at Stanford about three years ago now, though we've been physically operational just over two years and we're an independent research institute working at the interface of biomedical science and machine learning. And we have a few different aspects of our model, but our overall mission is to understand and treat complex human diseases. And we have three pillars to our model. We have this PI driven side of the house where we centrally fund our investigators so that they don't have to write grants and work on their very best ideas. We have a technical staff side of the house more like you'd see in a frontier AI lab or in biotech industry where we have professional teams of R&D scientists working cross-functionally on higher level organizational wide goals that we call our institute initiatives.(02:05):One focused on Alzheimer's disease experimentally and one that we call a virtual cell initiative to simulate human biology with AI foundation models. And our third pillar over time is to have things not just end up as academic papers, but really get things out into the real world as products or as medicines that can actually help patients on the translational side. And so, we thought that some really important scientific programs could be unlocked by enabling new organizational models and we are experimenting at the institutional scale with how we can better organize and incentivize and support scientists to reach these long-term capability breakthroughs.Patrick, Patrick and SilvanaEric Topol (02:52):So the two Patrick's. How did you, one Patrick I guess is a multi-billionaire from Stripe and then there's you who I suspect maybe not quite as wealthy as the other Patrick, how did you guys come together to do this extraordinary thing?Patrick Hsu (03:08):Yeah, no, science is certainly expensive. I met Patrick originally through Silvana actually. They actually met, so funny trivia, all three Arc founders did high school science together. Patrick and Silvana originally met in the European version of the European Young Scientist competition in high school. And Silvana and I met during our PhDs in her case at MIT and I was at Harvard, but we met at the Broad Institute sort of also a collaborative Harvard, MIT and Harvard hospitals Institute based in Kendall Square. And so, we sort of in various pairwise combinations known each other for decades and worked together for decades and have all collectively been really excited about science and technology and its potential to accelerate societal progress. Yet we also felt in our own ways that despite a lot of the tremendous progress, the structures in which we do this work, fund it, incentivize it and roll it out into the real world, seems like it's really possible that we'll undershoot that potential. And if you take 15 years ago, we didn't have the modern transformer that launched the current AI revolution, CRISPR technology, single-cell, mRNA technology or broadly addressable LNPs. That's a tremendous amount of technologies have developed in the next 15 years. We think there's a real unique opportunity for new institutes in the 2020s to take advantage of all of these breakthroughs and the new ones that are coming to continue to accelerate biological progress but do so in a way that's fast and flexible and really focused.Eric Topol (04:58):Yeah, I did want to talk with you a bit. First of all before I get to the next related topic, I get a kick out of you saying you've worked or known each other for decades because I think you're only in your early thirties. Is that right?Patrick Hsu (05:14):I was lucky to get an early start. I first started doing research at the local university when I was 14 actually, and I was homeschooled actually until college. And so, one of the funny things that you got to do when you're homeschooled is well, you could do whatever you want. And in my case that was work in the lab. And so, I actually worked basically full time as an intern volunteer, cut my teeth in single cell patch clamp, molecular biology, protein biochemistry, two photon and focal imaging and kind of spiraled from there. I loved the lab, I loved doing bench work. It was much more exciting to me than programming computers, which was what I was doing at the time. And I think these sort of two loves have kind of brought me and us to where we are today.Eric Topol (06:07):Before you got to Berkeley and Arc, I know you were at Broad Institute, but did you also pick up formal training in computer science and AI or is that something that was just part of the flow?Patrick Hsu (06:24):So I grew up coding. I used to work through problems sets before dinner growing up. And so, it's just something that you kind of learn natively just like learning French or Mandarin.New Models of Funding Life ScienceEric Topol (06:42):That's what I figured. Okay. Now this model of Arc Institute came along in a kind of similar timeframe as the Arena BioWorks in Boston, where some of the faculty left to go to Arena like my friend Stuart Schreiber and many others. And then of course Priscilla and Mark formed the Chan Zuckerberg Institute and its biohub and its support. So can you contrast for one, these three different models because they're both very different than of course the traditional NIH pathway, how Arc is similar or different to the others, and obviously the goal here is accelerating things that are going to really make a difference.Patrick Hsu (07:26):Yeah, the first thing I would say is zooming out. There have been lots of efforts to experiment with how we do science, the practice of science itself. And in fact, I've recently been reading this book, the Demon Under the Microscope about the history of infectious disease, and it talks about how in the 1910s through the 1930s, these German industrial dye manufacturing companies like Bayer and BASF actually launched what became essentially an early model for industrial scale science, where they were trying to develop Prontosil, Salvarsan and some of these early anti-infectives that targeted streptococcus. And these were some of the major breakthroughs that led to huge medical advances on tackling infectious disease compared to the more academic university bound model. So these trends of industrial versus academic labs and different structures to optimize breakthroughs and applications has been a through current throughout international science for the last century.(08:38):And so, the way that we do research today, and that's some of our core tenets at Arc is basically it hasn't always been this way. It doesn't need to necessarily be this way. And so, I think organizational experiments should really matter. And so, there's CZI, Altos, Arena, Calico, a variety of other organizational experiments and similarly we had MRC and Bell Labs and Xerox PARCS, NIBRT, GNF, Google Research, and so on. And so, I think there are lots of different ways that you can organize folks. I think at a high level you can think about ways that you can play with for-profit versus nonprofit structures. Whether you want to be a completely independent organization or if you want to be partnered with universities. If you want to be doing application driven science or really blue sky curiosity driven work. And I think also thinking through internally the types of expertise that you bring together.(09:42):You can think of it like a cancer institute maybe as a very vertically integrated model. You have folks working on all kinds of different areas surrounding oncology or immunotherapy and you might call that the Tower of Babel model. The other way that folks have built institutes, you might call the lily pad model where you have coverage of as many areas of biomedical research as possible. Places like the Whitehead or Salk, it will be very broad. You'll have planned epigenetics, folks looking at RNA structural biology, people studying yeast cell cycle, folks doing in vivo melanoma models. It's very broad and I think what we try to do at Arc is think about a model that you might liken more to overlapping Viking shields where there's sort of five core areas that we're deeply investing in, in genetics and genomics, computation, neuroscience, immunology and chemical biology. Now we really think of these as five areas that are maybe the minimal critical mass that you would need to make a dent on something as complicated as complex human diseases. It's certainly not the only thing that you need, but we needed a critical mass of investigators working at least in these areas.Eric Topol (11:05):Well, yeah, and they really converge on where the hottest advances are being made these days. Now can you work at Arc Institute without being one of these three universities or is it really that you maintain your faculty and your part of this other entity?Patrick Hsu (11:24):So we have a few elements to even just the academic side of the house. We have our core investigators. I'm one of them, where we have dually appointed faculty who retain their latter rank or tenured appointment in their home department, but their labs are physically cited at the Arc headquarters where we built out a lab in Stanford Research Park in Palo Alto. And so, folks move their labs there. They continue to train graduate students based on whatever graduate programs they're formally affiliated with through their university affiliation. And so, we have nearly 40 PhD students across our labs that are training on site every day.(12:03):So in addition to our core investigators, we also have what we call our innovation investigators, which is more of a grant program to faculty at our partner universities. They receive unrestricted funding from us to seed a new project or accelerate an existing area in their group and their labs stay at their home campus and they just get that funding to augment their work. The third way is our technical staff model where folks basically just come work at Arc and many of them also are establishing their own research groups focusing on technology R&D areas. And so, we have five of those technology centers working in molecular engineering, multi-omics, complex cellular models, in vivo models, and in machine learning.Discovery of Bridge RNAsEric Topol (12:54):Yeah, that's a great structure. In fact, just a few months ago, Patrick Collison, the other Patrick came to Stanford HAI where I'm on the board and you've summarized it really well and it's very different than the other models and other entities, companies included that you mentioned. It's really very impressive. Now speaking of impressive on June 26, this past few months ago, which incidentally is coincident with the draft genome in the year 2000, the human sequence. You and your colleagues, perhaps the most impressive jump in terms of an Arc Institute contribution published two papers back-to-back in Nature about bridge RNA: [Bridge RNAs direct programmable recombination of target and donor DNA] and [Structural mechanism of bridge RNA-guided recombination.] And before I get you to describe this breakthrough in genome editing, some would call it genome editing 3.0 or CRISPR 3.0, whatever. But what we have today in the clinic with the approval of CRISPR 1.0 for sickle cell and thalassemia is actually quite crude. I think most people will know it's just a double stranded DNA cleavage with all sorts of issues about repair and it's not very precise. And so, CRISPR 2.0 is supposed to be represented by David Liu's contributions and his efforts at Broad like prime and base editing and then comes yours. So maybe you can tell us about it and how it is has to be viewed as quite an important advance.Patrick Hsu (14:39):The first thing I would say before CRISPR, is that we had RNA interference. And so, even before this modern genome editing revolution with programmable CRISPRs, we had this technology that had a lot of the core selling points as well. Any target will now become druggable to us. We simply need to reprogram a guide RNA and we can get genetic access to things that are intracellular. And I think both the discovery of RNA interference by Craig Mello and Andy Fire or the invention or discovery of programmable CRISPR technologies, both depend on the same fundamental biological mechanism. These non-coding guide RNAs that are essentially a short RNA search string that you can easily reprogram to retarget a desired enzyme function, and natively both RNAi and CRISPR are molecular scissors. Their RNA or DNA nucleases that can be reprogrammed to different regions of the genome or the transcriptome to make a cut.(15:48):And as bioengineers, we have come up with all kinds of creative ways to leverage the ability to make site specific cuts to do all kinds of incredible things including genome editing or beyond transcriptional up or down regulation, molecular imaging and so on and so forth. And so, the first thing that we started thinking about in our lab was, why would mother nature have stopped only RNAi and CRISPR? There probably are lots of other non-coding RNAs out there that might be able to be programmable and if they did exist, they probably also do more complicated and interesting things than just guide a molecular scissors. So that was sort of the first core kind of intuition that we had. The second intuition that we had on the technology side, I was just wearing my biology hat, I'll put on my technology hat, is the thing that we call genome editing today hardly involves the genome.(16:50):It's really you're making a cut to change an individual base or an individual gene or locus. So really you're doing small scale single locus editing, so you might call it gene level or locus level cuts. And what you really want to be able to do is do things at the genome scale at 100 kb, a megabase at the chromosome scale. And I think that's where I think the field will inevitably go if you follow the technology curves of longer and longer range gene sequencing, longer and longer range gene synthesis, and then longer and longer range gene editing. And so, what would that look like? And we started thinking, could there be essentially recombination technologies that allow you to do cut and paste in a single step. Now, the reason for that is the way that we do gene editing today involves a cut and then a multi-step process of cellular DNA repair that resolves the cut to make the exertion or the error prone deletion or the modification that ends up happening.(17:59):And so, it's very complicated and whether that's nucleases or base or prime editing, you're all generally limited to the small-scale single locus changes. However, there are natural mechanisms that have solved this cut and paste problem, right? There are these viruses or bacterial versions of viruses known as phage that have generally been trying to exert their multi kilobase genomes into bacterial hosts and specialize throughout billions of years. So our core thought was, well, if there are these new non-coding RNAs, what kind of functions would we be excited about? Can we look in these mobile genetic elements, these so-called jumping genes for new mechanisms? They're incredibly widespread. Transposons are thought to be some of the most diverse enzyme mechanisms found in nature. And so, we started computationally by asking ourselves a very simple question. If a mobile element inserts itself into foreign DNA and it's able to somehow be programmable, presumably the inside or something encoded in the inside of the element is predictive of some sequence on the outside of the element.(19:15):And so, that was the core insight we took, and we thought let's look across the boundaries of many different mobile genetic elements and we zoomed in on a particular sub family of these MGE known as insertion sequence (IS) elements which are the most autonomous minimal transposons. Normally transposons have all kinds of genes that they use to hitchhike around the genomic galaxy and endow the bacterial host with some fitness advantage like some ability to metabolize some copper and some host or some metal. And these IS elements have only the enzymes that they need to jump around. And if you identify the boundaries of these using modern computational methods, this is actually a really non-trivial problem. But if you solve that problem to figure out with nucleotide resolution where the element boundaries end and then you look for the open reading frame of the transposases enzyme inside of this element, you'll find that it's not just that coding sequence.(20:19):There are also these non-coding flanks inside of the element boundaries. And when we looked across the non-coding, the entire IS family tree, there are hundreds of these different types of elements. We found that this particular family IS110, had the longest non-coding ends of all IS elements. And we started doing experiments in the lab to try to figure out how these work. And what we found was that these elements are cut and paste elements, so they excise themselves into a circular form and paste themselves back in into a target site linearly. But the circularization of this element brings together two distal ends together, which brings together a -35 and a -10 box that create and reconstitute a canonical bacterial transcriptional promoter. This essentially is like plugging a plug into an electrical socket in the wall and it jacks up transcription. Now you would think this transcription would turn on the transposase enzyme so it can jump around more but it transcribes a non-coding RNA out of this non-coding end.(21:30):We're like, holy crap, are these RNAs actually involved in regulating the transposon? Now the boring answer would be, oh, it regulates the expression. It's like an antisense regulate or something. The exciting answer would be, oh, it's a new type of guide RNA and you found an RNA guided integrase. So we started zooming in bound dramatically on this and we undertook a covariation analysis where we were able to show that this cryptic non-coding RNA has a totally novel guide RNA structure, totally distinct from RNAi or CRISPR guide RNAs. And it had a target site that covaried with the target site of the element. And so we're like, oh wow, this could be a programmable transposase. The second thing that we found was even more surprising, there was a second region of complementarity in that same RNA that recognized the donor sequence, which is the circularized element itself. And so, this was the first example of a bispecific guide RNA, and also the first example of RNA guided self-recognition by a mobile genetic element.Eric Topol (22:39):It's pretty extraordinary because basically you did a systematic assessment of jumping genes or transposons and you found that they contain things that previously were not at all recognized. And then you have a way to program these to edit, change the genome without having to do any cuts or nicks, right?Patrick Hsu (23:05):Yeah. So what we showed in a test tube is when we took this, so-called bridge RNA, which we named because it bridges the target and donor together along with the recombinase enzyme. So the two component system, those are the only two things that you need. They're able to cut and paste DNA and recombine them in a test tube without any DNA repair, meaning that it's independent of cellular DNA repair and it does strand nicking, exchange, junction resolution and religation all in a single mechanism. So that's when we got super excited about its potential applications as bioengineering tool.Eric Topol (23:46):Yeah, it's pretty extraordinary. And have you already gone into in vivo assessment?Patrick Hsu (23:54):Yes, in our initial set of papers, what we showed is that these are programmable and functional or recombinases in a test tube and in bacterial cells. And by reprogramming the target and donor the right way, you can use these enzymes not just for insertion, but also for flipping and cutting out DNA. And so, we actually have in a single mechanism the ability to do bridge editing, if you will, for universal DNA recombination, insertion, excision or inversion, similar to what folks have been doing for decades with Cre recombinase, but with fully programmable recognition sequences. The work that we're doing now in the lab as you can imagine is to adapt these into robust tools for mammalian genome editing, including of course, human genomes. We're excited about this, we're making good progress. The CRISPR has had thousands of labs over the last 10, 15 years working on it to make these therapeutic level potency and selectivity. We're going to work and follow that same blueprint for getting bridge systems to get to that level of performance, but we're on the path and we're very optimistic for the future.Exemplar of Digital BiologyEric Topol (25:13):Yeah, I think it's quite extraordinary and it's a whole different look to what we've been seeing in the CRISPR era for over the past decade and how that's been advancing and getting more specific and less need for repair and being able to be more versatile. But this takes it to yet another dimension. Now, this brings me to the field that when I think of this term digital biology, I think of you and now our mutual acquaintance, Jensen Huang, who everybody knows now. Back some months ago, he wrote and said at a conference, “Where do I think the next amazing revolution is going to come? And this is going to be flat out one of the biggest ones ever. There's no question that digital biology is going to be it. For the first time in human history, biology has the opportunity to be engineering, not science.” So can you critique Jensen? Is he right? And tell us how you conceive the field of digital biology.Patrick Hsu (26:20):If you look at gene therapy today, the core concepts are actually remarkably simple. They're elegant. Of course, you're missing a broken gene, you need to put it back. And that can be curative. Very simple, powerful concept. However, for complex diseases where you don't have just a single gene that goes wrong, in many cases we actually have no idea what to do. And in fact, when you're trying to put in DNA, that's over more than a gene scale. We kind of very quickly run out of ideas. Is it a CAR and a cytokine, a CAR and a cytokine and another thing? And then we're kind of out of ideas. And so, we started thinking in the lab, how can we actually design genomes where it's not just let's reduce the genome into individual Lego blocks, iGem style with promoters and different genes that we just sort of shuffle the Lego blocks around, but actually use AI to design genome sequences.(27:29):So to do that, we thought we would have to first of all, train a model that can learn and decode the foreign language of biology and use that in order to design sequences. And so, we sort of have been training DNA foundation models and virtual cell models at Arc, sort of a major effort of ours where the first thing that we tried was to take a variance of transformer architecture that's used to train ChatGPT from OpenAI, but instead apply this to study the next DNA token, right? Now, the interesting thing about next token prediction in English is that you can actually learn a surprising amount of information by just predicting the next word. You can learn world knowledge is the capital of Azerbaijan, is it Baku or is it London, right? Or if you're walking around in the kitchen, then the next text is, I then left the kitchen or the bathroom, right?(28:33):Now you're learning about spatial reasoning, and so you can also learn translation obviously. And so similarly, I think predicting the next token or the next base and DNA can lead you to learn about molecular biochemistry, is the next amino acid residue, hydrophobic or hydrophilic. And it can teach you about the mechanics of some catalytic binding pocket or something. You can learn about a disease mutation. Is the next base, the sick linked base or the wild type base and so on and so forth. And what we found was that at massive scale, DNA foundation models learn about molecular function, not just at the DNA level, but also at the RNA and the protein. And indeed, we could use these to design molecular systems like CRISPR-Cas systems, where you have a protein and the guide RNA. It could also design new DNA transposons, and we could design sequences that look plausibly like real genomes, where we generate a megabase a million bases of continuous genome sequence. And it really looks and feels like it could be a blurry picture of something that you would actually sequence. This has been a wonderful collaboration with Brian Hie, a PI at Stanford and an Arc investigator, and we're really excited about what we've seen in this work because it promises the better performance with even more scale. And so, simply by scaling up these models, by adding in more compute, more training data or more powerful models, they're going to get sharper and sharper.New A.I. Models in Life ScienceEric Topol (30:25):Yeah. Well, this whole use of large language models for the language of life, whether it's the genome proteins and on and on, actually RNA and even cells has really taken root. And of course, this is really one of the foundations of that field of digital biology, which brings together generative AI, AI tools and trying to push forward our understanding in biology. And also, obviously what's been emphasized in drug discovery, perhaps it's been emphasized even too much because we still have a lot to learn about biology, but that gets me to these models. Like today, AlphaProteo was announced by DeepMind, as we all know, AlphaFold 1, 2, now 3. They were kind of precursors of being able to predict proteins from amino acid 3D structure. And that kind of took the field by a little bit like ChatGPT for life science, but now it's a new model all the time. So you've been working on various models and Arc Institute, how do you see this unfolding? Are we just going to have every aspect of the language of life being approached in all the different interactions? And this is going to help us get to a much more deep level of understanding.Patrick Hsu (31:56):I'll say two things. The first is a lot of models that you just described are what I would call task specific models. A model for de novo design of a binder, a model for protein structure prediction. And there are other models for protein fitness or for RNA structure prediction, et cetera, et cetera. And I think what we're going to move towards are more unifying models where there's different classes of models at different levels of scale. So we will have these atomic level models for looking at generative chemistry or ligand docking. We have models that can unify genomes and their molecules, and then we have models that can unify cells and tissues. And so, for example, if you took an H&E stain of some liver, there are folks building models where you can then predict what the single cell spatial transcriptome will look like of that model. And that's obviously operating at a very different level of abstraction than a de novo protein binder. But in the long run, all of these are going to get, I think unified. I think the reason why this is possible is that biology, unlike physics, actually has this unifying theory of evolution that runs across all of its length scales from atomic, molecular, cellular, organismal to entire ecosystem. And the promise of these models is no short then to make biology a predictive discipline.Patrick Hsu (33:37):In physics, the experimentalists win the big prizes for the theorists when they measure gravitational waves or whatever. But in biology, we're very practical people. You do something three times and do a T-test. And I think my prediction is we can actually gauge the success of these LLMs or whatever in biology by how much we respect theory in this field.The A.I. ScientistEric Topol (34:05):Yeah. Well, that's a really interesting perspective, an important perspective because the proliferation of models, which we're going to get into not just doing the things that you described, but also being able to be “pseudo” scientists, the so-called AI scientist. Maybe you could comment about that concept because that's been the idea that everything from the question that could be asked to the hypothesis and the experiment design and the analysis of data and then the feedback. So what is the role of the scientists, that seems to have been overplayed? And maybe you can put that in context.Patrick Hsu (34:48):So yeah, right now there's a lot of excitement that we can use AI agents not just to do software enterprise workflows, but to be a research assistant. And then over time, itself an autonomous research scientist that can read the literature, come up with an idea, maybe run a bunch of robots in the lab or do a bunch of computational analyses and then potentially even analyze data, conclude what is going on and actually write an entire paper. Now, I think the vision of this is compelling in the long term. I think the question is really about timescale. If you break down the scientific method into its constituent parts, like hypothesis generation, doing an experiment, analyzing experiment and iterating, we're clearly going to use AI of some kind at every single step of this cycle. I think different steps will require different levels of maturity. The way that I would liken this is just wet lab automation, folks have dreamed about having pipetting robots that just do their western blots and do their cell culture for them for generations.(36:01):But of course, today they don't actually really feel fundamentally different from the same ones that we had in the 90s, let's say. Right? And so, obviously they're getting better, but it seems to me one of the trends I'm very bullish about is the explosion of humanoid robots and robot foundation models that have a world model and a sense of physics and proportionate space loaded onto them. Within five years, we're going to have home robots that can fold your clothes, that can organize your kitchen and do all of this while you're sleeping, so you wake up to a clean home every day.Eric Topol (36:40):It's not going to be just Roomba anymore. There's going to be a lot more, but it isn't just the hardware, it's also the agents playing in software, right?Patrick Hsu (36:50):It's the integrated loop of the hardware and the software where the ability to make the same machine generally intelligent will make it adaptable to a broad array of tasks. Now, what I'm excited about is those generally intelligent humanoid robots coming into the lab, where instead of creating a centrifuge or a new type of pipetter that's optimized for your Beckman or Hamilton device, instead you just have robot arms that you snap onto the edge of the bench and then they just work alongside you. And I do think that's coming, although it'll take a lot of hardware and software and computer vision engineering to make that possible.A Sense of HumorEric Topol (37:32):Yeah, and I think also going back to originating the question, there still is quite a debate about the creativity and the lack of any simulation of AGI, whatever that means anymore. And so, the human in the loop part of this is obviously I think it's still of critical nature. Now, the other thing I learned about you is you have a great sense of humor, which is really important by the way. And recently, which is great that you're active on X or Twitter because that's one way we get to see what you're thinking on a day-to-day basis. But I think you put out a poll which was really quite provocative , and it was about, here's what it said, “do more people in the world *truly* understand transformers or health insurance?” And interestingly, you got 49% for transformers at 51% for health insurance. Can you tell us what you're thinking when you put that poll together? Because obviously a lot of people don't understand either of these.Patrick Hsu (38:44):I think the core question is, there are different ways of looking at the world, some of which are very bottom up and some of which are very top down. And one of the very surprising things about transformers is they're taking something that is in principle, an incredibly simple task, which is if you have a string of text, what is the next letter? And somehow at massive, massive scale, you can unlock something that looks an awful lot like reasoning, and you've got these emergent behaviors. Now the bottoms up theory of just the linear algebra that's going on in these models couldn't possibly really help us predict that we have these emerging capabilities. And I think similarly in healthcare, there's a literal set of parts that are operating in some complex way that at massive scale becomes this incredibly confusing and dynamic system for how we can actually incentivize how we make medicines, how we actually take care of people, and how we actually pay for any of this from an economic point of view. And so, I think it was, in some sense if transformers can actually be an explainable by just linear algebra equations, maybe there will be a way to decompose the seemingly incredibly confusing world of healthcare in order to actually build a better way forward.Computing Power and the GPU Arms RaceEric Topol (40:12):Yeah. Well that's great. Now the other thing I wanted to ask you about, we open source and the arms race of GPUs and this whole kind of idea is you touched on the need for coalescing a lot of these tools to exploit the synergy. But we have an issue because many academic labs like here at Scripps Research and so many others, including as I learned even at Stanford, have limited access to GPUs. So computing power of large language models is a problem. And then the models that exist today that can be adopted like Llama or others, and they're somewhat limited. And then we also have a movement towards trying to make things more open source, like for example, recently OpenCRISPR with Profluent Bio that is basically trying to use AI for CRISPR guides. And so, how do you deal with this arms race, computing power, open source, proprietary models that are not easily accessible without a lot of resources?Patrick Hsu (41:30):So the first thing I would say is, we are in the academic science sphere really unprepared for the level of resources that are required for doing this type of cutting edge computational work. There are top Stanford computer science professors or computational researchers who have a single GPU in their office, and that's actually what their whole lab runs off of.(41:58):The UC Berkeley campus, the grid runs on something like 12 megawatts of power and how are they going to build an on-premises GPU clusters, like a central question that can scale across the entire needs? And these are two of the top computer science universities in the world. And so, I think one of our kind of core beliefs at Arc is, as science both experimentally and computationally has gotten incredibly complex, not just in terms of conceptually, but also just the actual infrastructure and machines and know-how that you need to do things. We actually need to essentially support this. So we have a private GPU cloud that we use to train our models, and we have access to significantly large clusters for large burst kind of train outs as necessary. And I think infrastructurally for running genomics experiments or doing scalable brain organoid screens, right, we're also building out the infrastructure to support that experimentally.Eric Topol (43:01):Yeah, no, I think this is one of the advantages of the new model like the Arc Institute because not many centers have that type of plasticity with access to computing power when needed. So that's where a brilliant mind you and the Arc Institute together makes for a formidable recipe for future advances and of course building on the ones you've already accomplished.The Primacy of Human TalentPatrick Hsu (43:35):I would just say, my main skill, if I have one, is to recruit really, really smart people. And so, everything that you're seeing and hearing about is the work of unbelievable colleagues who are curious, passionate, and incredible scientists.Eric Topol (43:53):But it also takes the person who can judge those who are in that category set as a role model. And you're certainly doing that. I guess just in closing, I mean, it's just such a delight to get to meet you here and kind of get your thoughts on what is the hottest thing in life science without question, which brings together the fields of AI and what's going on, not just obviously in genome editing, but this digital biology era that we're still in the early phases of, I mean, I think you could say that it's just going to continue to accelerate the exponential curve. We're still kind of on the bottom of that, I would imagine where we're headed. Any other things that you want to bring up that I haven't touched on that will round out this conversation?Patrick Hsu (44:50):I mean, I think it's very early days here at Arc.Patrick Hsu (44:53):When we founded Arc, we asked ourselves, how do we measure success? We don't have customers or revenue in the way that a typical startup does. And we felt sort of three things. The first was research institutes live and die by their talent. Can we actually hire incredible people when we make offers to people we want to come, do they come? The second was, when those folks do come to Arc, do they feel like they're able to work on important research programs that they couldn't do sort of at their prior university or company? And then longer term, the third thing was, and there's just no shortcut around this, you need to do important work. And I think we've been really excited that there are early signs that we're able to do all three of these things, and we're still, again, just following the same scaling laws that we're seeing in natural language and vision, but for the domain of biology. And so, we're excited about what's ahead and think if there are folks who are interested in learning more about Arc, just shoot me an email or DM.Eric Topol (46:07):Yeah, well I would just say, congratulations on what you've already achieved. I know you're going to keep rocking it because you already have in a short time. And for anybody who doesn't know about Arc Institute and your work and your team, I hope this is going to be putting them on notice actually what can be accomplished outside of the usual NIH funded model, which is kind of a risk-free zone where you basically have to have your results nailed down before you send in your proposal frequently, and it doesn't do great things for young people. Really, I think you actually qualify in that demographic where it's hard for them to break in for getting NIH grants and also for this type of work that you're doing. So we'll look for the next bridge beyond bridge RNAs of your just fantastic efforts. So Patrick, thanks so much for joining us today, and we'll be checking back with you and following all the great work that you'll be doing in the times ahead.Patrick Hsu (47:14):Thanks so much, Eric. It was such a pleasure to be here today. Appreciate the opportunity.*******************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly help fund our summer internship programs.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

An introduction to the processes by which cells control which genes are expressed. We begin with an overview of why genetic regulation is necessary and the key stages where such regulation occurs, including key concepts such as transcription factors and DNA binding domains. We then discuss prokaryotic gene regulation, focusing on the lac operon in E. coli. We then expand the discussion to cover the various mechanisms of eukaryotic gene regulation, including chromatic remodelling, transcriptional regulation, post-transcriptional regulation, RNA editing, and micro RNAs. Recommended pre-listening is Episodes 34-35: DNA Structure and Function, and Episode 118: Cell Signalling. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Fun With CellxGene, published by sarahconstantin on September 9, 2024 on LessWrong. For this week's post, I thought I'd mess around a bit with the CellXGene tool provided by the Chan Zuckerberg Institute. It's based on a big dataset of individual cells, classified by tissue, cell type, and disease state, and their gene expression profiles (single-cell RNA counts). You can automatically compare how gene expression looks different between sick and healthy individuals, for a variety of diseases, and drill down into which cells/tissues are different and how. It's a fascinating toy and a great way to generate hypotheses. Here, I'll do it for Alzheimer's, comparing 138,438 Alzheimer's brain cells to 9,203,998 normal/healthy brain cells to see what the most "differentially expressed" genes are, and what that might tell us about how the disease works. Top Hits LINC01609 1.6x overexpressed in Alzheimer's, d =4.203 This is a non-protein coding RNA. Typically most expressed in the testis. In CellxGene's healthy brain cells, it's expressed only in activated microglia and astrocytes; but in the Alzheimer's brain, it's expressed in roughly half of all types of cells. Like many long non-coding RNAs, its function is unknown. SLC26A3 10.6x overexpressed in Alzheimer's, d = 3.310 This is a chloride anion exchanger, a membrane protein that transports chloride ions across the cell membrane. It's most heavily expressed in the colon, where it controls the resorption of fluid from the intestines. Defects in this gene are associated with congenital diarrhea, as the body is unable to maintain the right osmotic concentration and loses water in the stool. But we're interested in SLC26A3 in the brain, not in the intestine. In the healthy brain, once again, it's only expressed in activated astrocytes and microglia; in the Alzheimer's brain it's expressed in large numbers of all cell types. CellxGene classifies it as one of the top "markers" for mature astrocytes and mature microglial cells, with a specificity of 1.00. Other researchers have observed the upregulation of SLC26A3 in Alzheimer's, e.g. as part of a pattern of "gliovascular" alteration around the clusters of astrocytes and endothelial cells that control the blood-brain barrier.1 A gliovascular unit is the place a blood vessel meets the brain. The vessel is surrounded by astrocytes and microglia, which control what goes in and out of the bloodstream, clearing excess glutamate and misfolded proteins. Under prolonged stress, these astrocytes in gliovascular units become reactive, and ultimately the blood-brain barrier breaks down. In Alzheimer's disease, the blood vessels get narrower, fragment, and break.2 Activated astrocytes no longer connect as tightly to the surface of the vessels with their "endfeet", compromising the BBB, while activated microglia engulf the endfeet, exacerbating the effect.3 What actually happens if you have more chloride anion exchange in the cells of a gliovascular unit? Is it causal for any Alzheimer's pathology? That, I don't think we know. RASGEF1B 5.5x overexpressed in Alzheimer's, d=3.267 This is a widely expressed cytoplasmic protein that allows the protein Ras to be "switched on", sending intracellular signals that lead to cell growth, differentiation, and survival. 4 Once again, in the healthy brain it is only expressed in activated astrocytes and microglia, while in the Alzheimer's brain it's expressed everywhere. CellxGene classifies it as the top "marker" for mature astrocytes and mature microglial cells, with a specificity of 1.00. In normal circumstances, astrocytes and microglia can grow and proliferate, but most neurons do not. Ras activity increases in conditions of neural stress or injury, as part of the body's attempt to promote cell survival and neurite regeneration. So it makes sense that we...

In this episode of The Shift with CJ, CJ explores the fascinating world of epigenetics and its profound impact on health, longevity, and overall well-being. Epigenetics, the study of how behavior and environment can alter gene expression without changing the DNA sequence, is described as the "director" of our genetic "script." CJ breaks down complex scientific concepts like DNA methylation, histone modifications, and non-coding RNAs, explaining how they influence aging and disease. The episode also delves into practical lifestyle changes and biohacks that can positively impact epigenetic regulation, promoting a longer and healthier life.Key Takeaways:Understanding Epigenetics: Your DNA acts as the script of your life, but epigenetics, influenced by your environment and behavior, determines how that script plays out. It's like a light switch that can turn certain genes on or off, impacting your health and longevity.DNA Methylation and Histone Modifications: These are crucial processes that influence gene expression. While DNA methylation can silence or activate genes, histone modifications help in the packaging of DNA, which affects how genes are expressed. Both are heavily influenced by lifestyle factors.Impact of Non-Coding RNAs: These molecules, although not translated into proteins, play a significant role in regulating gene expression, impacting everything from aging to disease susceptibility.Lifestyle is Key: Supplements and biohacks are helpful, but the foundation of good health starts with a healthy lifestyle. This includes a nutrient-rich diet, proper sleep, regular exercise, and stress management.Practical Biohacks: From consuming polyphenol-rich foods like berries and green tea to using cutting-edge techniques like pulsed electromagnetic field therapy (PEMF) and infrared saunas, CJ discusses various methods to enhance your epigenetic health.5 Actionable Steps to Improve Your Life:Incorporate Folate into Your Diet: Folate-rich foods like leafy greens and legumes support DNA methylation, which is crucial for healthy gene expression.Consume Polyphenol-Rich Foods: Berries, green tea, dark chocolate, and red wine contain polyphenols that positively influence epigenetics. Moderation is key, especially with red wine.Add Cruciferous Vegetables: Broccoli, cauliflower, and other cruciferous vegetables contain sulforaphane, which helps modulate histone deacetylase activity, promoting healthy aging.Explore Infrared Saunas: Regular use of infrared saunas can support longevity by promoting positive gene expression changes and detoxification.Consider PEMF Therapy: This advanced biohack uses electromagnetic fields to improve cellular health and influence gene expression, offering benefits similar to grounding but with enhanced effects.This episode emphasizes the importance of understanding and influencing your epigenetics to achieve optimal health. By making small, consistent lifestyle changes and exploring biohacking techniques, you can take control of your biology and live a longer, healthier life.

We love to hear from our listeners. Send us a message. Flagship Pioneering's ProFound Therapeutics is on to something, and it could be something big. It began with a simple question:  What if more RNAs were being translated into proteins? Answering that question took ProFound deep into the translatome, where it's now studying the full compendium of RNA sequences that are being translated into proteins. Along the way, the young company is gaining confidence that its research will reveal important insight into potential therapeutic protein targets and medicines. On this episode of the Business of Biotech, ProFound CEO and Flagship Pioneering CEO-Partner John Lepore, M.D. shares the company's journey—and his—as a physician scientist-turned-founder.Register for Bioprocess Online's Bio Expo Live, being held July 30th through August 1st . This inaugural expo is a fantastic opportunity for biopharma companies and contract manufacturers to evaluate the latest and greatest from the comfort of your desktop or mobile device. Conveniently, we've broken down the lineup into Upstream Solutions July 30th, Downstream Solutions July 31st, and Quality, Analytical, and Data Solutions August 1st. It's absolutely free to register for this series of short, digestible, and interactive sessions -- just hit the links above to register for Bio Expo Live today!

In this episode of the Epigenetics Podcast, we talked with Claire Rougeulle from the Epigenetics and Cell Fate Center at Université Paris City on this show to talk about her work on gene expression control, the intricacies of X-chromosome inactivation, and the potential of non-coding RNAs in this process. In this episode Claire Rougeulle explains her discoveries regarding the transcription regulation of XIST by factors like YY1 and the erosion of X-chromosome inactivation in human pluripotent stem cells. She shares the complexity of distinguishing between epigenetics and transcriptional regulation, highlighting the challenges in studying allelic expression of X-chromosomes at the single-cell level. The Episode further explores Claire's findings on the XACT locus regulation, evolution from retroviruses, and its potential role in preventing X-chromosome silencing. Claire also shares her future research focus on understanding X-inactivation establishment in humans and the transition from XIST attenuating to silencing X-chromosomes after implantation.   References Makhlouf, M., Ouimette, J. F., Oldfield, A., Navarro, P., Neuillet, D., & Rougeulle, C. (2014). A prominent and conserved role for YY1 in Xist transcriptional activation. Nature communications, 5, 4878. https://doi.org/10.1038/ncomms5878 Vallot, C., Ouimette, J. F., Makhlouf, M., Féraud, O., Pontis, J., Côme, J., Martinat, C., Bennaceur-Griscelli, A., Lalande, M., & Rougeulle, C. (2015). Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape. Cell stem cell, 16(5), 533–546. https://doi.org/10.1016/j.stem.2015.03.016 Casanova, M., Moscatelli, M., Chauvière, L. É., Huret, C., Samson, J., Liyakat Ali, T. M., Rosspopoff, O., & Rougeulle, C. (2019). A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in humans. Nature communications, 10(1), 5652. https://doi.org/10.1038/s41467-019-13551-1   Related Episodes Epigenetics and X-Inactivation (Edith Heard) Investigating the Dynamics of Epigenetic Plasticity in Cancer with Single Cell Technologies (Céline Vallot)   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

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Multiplex Gene Editing: Where Are We Now?, published by sarahconstantin on July 16, 2024 on LessWrong. We're starting to get working gene therapies for single-mutation genetic disorders, and genetically modified cell therapies for attacking cancer. Some of them use CRISPR-based gene editing, a new technology (that earned Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize) to "cut" and "paste" a cell's DNA. But so far, the FDA-approved therapies can only edit one gene at a time. What if we want to edit more genes? Why is that hard, and how close are we to getting there? How CRISPR Works CRISPR is based on a DNA-cutting enzyme (the Cas9 nuclease), a synthetic guide RNA (gRNA), and another bit of RNA (tracrRNA) that's complementary to the gRNA. Researchers can design whatever guide RNA sequence they want; the gRNA will stick to the complementary part of the target DNA, the tracrRNA will complex with it, and the nuclease will make a cut there. So, that's the "cut" part - the "paste" comes from a template DNA sequence, again of the researchers' choice, which is included along with the CRISPR components. Usually all these sequences of nucleic acids are packaged in a circular plasmid, which is transfected into cells with nanoparticles or (non-disease-causing) viruses. So, why can't you make a CRISPR plasmid with arbitrary many genes to edit? There are a couple reasons: 1. Plasmids can't be too big or they won't fit inside the virus or the lipid nanoparticle. Lipid nanoparticles have about a 20,000 base-pair limit; adeno-associated viruses (AAV), the most common type of virus used in gene delivery, has a smaller payload, more like 4700 base pairs. 1. This places a very strict restriction on how many complete gene sequences that can be inserted - some genes are millions of base pairs long, and the average gene is thousands! 2. but if you're just making a very short edit to each gene, like a point mutation, or if you're deleting or inactivating the gene, payload limits aren't much of a factor. 2. DNA damage is bad for cells in high doses, particularly when it involves double-strand breaks. This also places limits on how many simultaneous edits you can do. 3. A guide RNA won't necessarily only bind to a single desired spot on the whole genome; it can also bind elsewhere, producing so-called "off-target" edits. If each guide RNA produces x off-target edits, then naively you'd expect 10 guide RNAs to produce 10x off-target edits…and at some point that'll reach an unacceptable risk of side effects from randomly screwing up the genome. 4. An edit won't necessarily work every time, on every strand of DNA in every cell. (The rate of successful edits is known as the efficiency). The more edits you try to make, the lower the efficiency will be for getting all edits simultaneously; if each edit is 50% efficient, then two edits will be 25% efficient or (more likely) even less. None of these issues make it fundamentally impossible to edit multiple genes with CRISPR and associated methods, but they do mean that the more (and bigger) edits you try to make, the greater the chance of failure or unacceptable side effects. How Base and Prime Editors Work Base editors are an alternative to CRISPR that don't involve any DNA cutting; instead, they use a CRISPR-style guide RNA to bind to a target sequence, and then convert a single base pair chemically - they turn a C/G base pair to an A/T, or vice versa. Without any double-strand breaks, base editors are less toxic to cells and less prone to off-target effects. The downside is that you can only use base editors to make single-point mutations; they're no good for large insertions or deletions. Prime editors, similarly, don't introduce double-strand breaks; instead, they include an enzyme ("nickase") that produces a single-strand "nick"...

Dr. Tassa Saldi is an accomplished molecular biologist with more than 25 years of research experience in RNA biology, infectious disease, and molecular pathogen detection. Dr. Saldi graduated Summa Cum Laude with a degree in Molecular Biology. She completed her graduate and postdoctoral studies at the University of Colorado, where she studied RNA structure, small RNAs and RNA processing. She was awarded a prestigious fellowship from the American Cancer Society and was one of eighteen doctoral fellows nationwide invited to present her research at the Aspen Cancer Conference.  Dr. Saldi has authored more than 20 peer-reviewed articles in top-tier journals. As the Chief Science Officer and co-founder of TUMI Genomics, Dr. Saldi continues to use her expertise to provide the cannabis industry with reliable, accurate diagnostic tools and pathogen mitigation guidance. 

Die Themen in den Wissensnachrichten: +++ Reifenabrieb im Salat nachgewiesen +++ Optimale Drehung für Bier-Tornado gefunden +++ Blutwurst aus der Bronzezeit entdeckt +++**********Zusätzliche InformationenUptake of tire-derived compounds in leafy vegetables and implications for human dietary exposure, Frontiers in Environmental Research, 28.5.2024Unravelling social status in the first medieval military order of the Iberian Peninsula using isotope analysis, Nature, 14.5.2024Impact of rotation change on the emptying of an ideal bottle of water, Physical Review Fluids, 4.6.2024Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs, Nature, 5.6.2024Biodegradation of polyethylene by the marine fungus Parengyodontium album, Science of The Total Environment, 15.7.2024Cauldrons of Bronze Age nomads reveals 2700 year old yak milk and the deep antiquity of food preparation techniques, Nature, 5.6.2024**********Ihr könnt uns auch auf diesen Kanälen folgen: Tiktok und Instagram.

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

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Professor Doudna was awarded the 2020 Nobel Prize in Chemistry with Professor Emmanuelle Charpentier for their pioneering work in CRISPR genome editing. The first genome editing therapy (Casgevy) was just FDA approved, only a decade after the CRISPR-Cas9 editing system discovery. But It's just the beginning of a much bigger impact story for medicine and life science.Ground Truths podcasts are now on Apple and Spotify. And if you prefer videos, they are posted on YouTubeTranscript with links to audio and relevant external linksEric Topol (00:06):This is Eric Topol with Ground Truths, and I'm really excited today to have with me Professor Jennifer Doudna, who heads up the Innovative Genomics Institute (IGI) at UC Berkeley, along with other academic appointments, and as everybody knows, was the Nobel laureate for her extraordinary discovery efforts with CRISPR genome editing. So welcome, Jennifer.Jennifer Doudna (00:31):Hello, Eric. Great to be here.Eric Topol (00:34):Well, you know we hadn't met before, but I felt like I know you so well because this is one of my favorite books, The Code Breaker. And Walter Isaacson did such a wonderful job to tell your story. What did you think of the book?My interview with Walter Isaacson on The Code Breaker, a book I highly recommendJennifer Doudna (00:48):I thought Walter did a great job. He's a good storyteller, and as you know from probably from reading it or maybe talking to others about it, he wrote a page turner. He actually really dug into the science and all the different aspects of it that I think created a great tale.Eric Topol (01:07):Yeah, I recommended highly. It was my favorite book when it came out a couple years ago, and it is a page turner. In fact, I just want to read one, there's so many quotes out of it, but in the early part of the book, he says, “the invention of CRISPR and the plague of Covid will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery beginning just over a century ago, of the three fundamental kernels of our existence, the atom, the bit, and the gene.” That kind of tells a big story just in one sentence, but I thought I'd start with the IGI, the institute that you have set up at Berkeley and what its overall goals are.Jennifer Doudna (01:58):Right. Well, let's just go back a few years maybe to the origins of this institute and my thinking around it, because in the early days of CRISPR, it was clear that we were really at a moment that was quite unique in the sense that there was a transformative technology. It was going to intersect with lots of other discoveries and technologies. And I work at a public institution and my question to myself was, how can I make sure that this powerful tool is first of all used responsibly and secondly, that it's used in a way that benefits as many people as possible, and it's a tall order, but clearly we needed to have some kind of a structure that would allow people to work together towards those goals. And that was really the mission behind the IGI, which was started as a partnership between UC Berkeley and UCSF and now actually includes UC Davis as well.The First FDA Approved Genome EditingEric Topol (02:57):I didn't realize that. That's terrific. Well, this is a pretty big time because 10 years or so, I guess starting to be 11 when you got this thing going, now we're starting to see, well, hundreds of patients have been treated and in December the FDA approved the first CRISPR therapy for sickle cell disease, Casgevy. Is that the way you say it?Jennifer Doudna (03:23):Casgevy, yeah.Eric Topol (03:24):That must have felt pretty good to see if you go from the molecules to the bench all the way now to actually treating diseases and getting approval, which is no easy task.Jennifer Doudna (03:39):Well, Eric, for me, I'm a biochemist and somebody who has always worked on the fundamentals of biology, and so it's really been extraordinary to see the pace at which the CRISPR technology has been adopted, and not just for fundamental research, but also for real applications. And Casgevy is sort of the crowning example of that so far, is that it's really a technology that we can already see how it's being used to, I think it's fair to say, effectively cure a genetic disease for the first time. Really amazing.Genome Editing is Not the Same as Gene TherapyEric Topol (04:17):Yeah. Now I want to get back to that. I know there's going to be refinements about that. And of course, there's beta thalassemia, so we've got two already, and our mutual friend Fyodor Urnov would say two down 5,000 to go. But I think before I get to the actual repair of the sickle cell defect molecular defect, I think one of the questions I think that people listeners may not know is the differentiation of genome editing with gene therapy. I mean, as you know, there was recently a gene therapy approval for something like $4.25 million for metachromatic leukodystrophy. So maybe you could give us kind of skinny on how these two fundamental therapies are different.Jennifer Doudna (05:07):Right. Well, it's a great question because the terminology sounds kind of the same, and so it could be confusing. Gene therapy goes back decades, I can remember gene therapy being discussed as an exciting new at the time, direction back when I was a graduate student. That was little while ago. And it refers to the idea that we can use a genetic approach for disease treatment or even for a cure. However, it fundamentally requires some mechanism of integrating new information into a genome. And traditionally that's been done using viruses, which are great at doing that. It's just that they do it wherever they want to do it, not necessarily where we want that information to go. And this is where CRISPR comes in. It's a technology allows precision in that kind of genetic manipulation. So it allows the scientist or the clinician to decide where to make a genetic change. And that gives us tremendous opportunity to do things with a kind of accuracy that hasn't been possible before.Eric Topol (06:12):Yeah, no question. That's just a footnote. My thesis in college at University of Virginia, 1975, I'm an old dog, was prospects for gene therapy in man. So it took a while, didn't it? But it's a lot better now with what you've been working on, you and your colleagues now and for the last decade for sure. Now, what I was really surprised about is it's not just of course, these hemoglobin disorders, but now already in phase two trials, you've got hereditary angioedema, which is a life-threatening condition, amyloidosis, cancer ex vivo, and also chronic urinary tract infections. And of course, there's six more others like autoimmune diseases like lupus and type 1 diabetes. So this is really blossoming. It's really extraordinary.Eric Topol (07:11):I mean, wow. So one of the questions I had about phages, because this is kind of going back to this original work and discovery, antimicrobial resistance is really a big problem and it's a global health crisis, and there's only two routes there coming up with new drugs, which has been slow and not really supported by the life science industry. And the other promising area is with phages. And I wonder, since this is an area you know so well, why haven't we put more, we're starting to see more trials in phages. Why haven't we doubled down or tripled down on this to help the antimicrobial resistance problem?Jennifer Doudna (08:00):Well, it's a really interesting area, and as you said, it's kind of one of those areas of science where I think there was interest a while ago and some effort was made for reasons that are not entirely clear to me, at least it fizzled out as a real focused field for a long time. But then more recently, people have realized that there's an opportunity here to take advantage of some natural biology in which viruses can infect and destroy microbes. Why aren't we taking better advantage of that for our own health purposes? So I personally am very excited about this area. I think there's a lot of fundamental work still to be done, but I think there's a tremendous opportunity there as well.CRISPR 2.0Eric Topol (08:48):Yeah, I sure think we need to invest in that. Now, getting back to this sickle cell story, which is so extraordinary. This is kind of a workaround plan of getting fetal hemoglobin built up, but what about actually repairing, getting to fixing the lesion, if you will?Eric Topol (09:11):Yeah. Is that needed?Jennifer Doudna (09:13):Well, maybe it's worth saying a little bit about how Casgevy works, and you alluded to this. It's not a direct cure. It's a mechanism that allows activation of a second protein called fetal hemoglobin that can suppress the effect of the sickle cell mutation. And it's great, and I think for patients, it offers a really interesting opportunity with their disease that hasn't been available in the past, but at the same time, it's not a true cure. And so the question is could we use a CRISPR type technology to actually make a correction to the genetic defect that directly causes the disease? And I think the answer is yes. The field isn't there quite yet. It's still relatively difficult to control the exact way that DNA editing is occurring, especially if we're doing it in vivo in the body. But boy, many people are working on this, as you probably know. And I really think that's on the horizon.Eric Topol (10:19):Yeah. Well, I think we want to get into the in vivo story as well because that, I think right now it's so complicated for a person to have to go through the procedure to get ultimately this treatment currently for sickle cell, whereas if you could do this in vivo and you could actually get the cure, that would be of the objective. Now, you published just earlier this month in PNAS a wonderful paper about the EDVs and the lipid nanoparticles that are ways that we could get to a better precision editing. These EDVs I guess if I have it right, enveloped virus-like particles. It could be different types, it could be extracellular vesicles or whatnot. But do you think that's going to be important? Because right now we're limited for delivery, we're limited to achieve the right kind of editing to do this highly precise. Is that a big step for the future?Jennifer Doudna (11:27):Really big. I think that's gating at the moment. Right now, as you mentioned, somebody that might want to get the drug Casgevy for sickle cell disease or thalassemia, they have to go through a bone marrow transplant to get it. And that means that it's very expensive. It's time consuming. It's obviously not pleasant to have to go through that. And so that automatically means that right now that therapy is quite restricted in the patients that it can benefit. But we imagine a day when you could get this type of therapy into the body with a one-time injection. Maybe someday it's a pill that could be taken where the gene editors target the right cells in the body. In diseases like that, it would be the stem cells in the bone marrow and carry out gene editing that can have a therapeutic benefit. And again, it's one of those ideas that sounds like science fiction, and yet already there's tremendous advance in that direction. And I think over the next, I don't know, I'm guessing 5 to 10 years we're going to see that coming online.Editing RNA, the Epigenome, and the MicrobiomeEric Topol (12:35):Yeah, I'm guessing just because there's so much work on the lipid nanoparticles to tweak them. And there's four different components that could easily be made so much better. And then all these virus-like proteins, I mean, it may happen even sooner. And it's really exciting. And I love that diagram in that paper. You have basically every organ of the body that isn't accessible now, potentially that would become accessible. And that's exciting because whatever blossoming we're seeing right now with these phase two trials ongoing, then you basically have no limits. And that I think is really important. So in vivo editing big. Now, the other thing that's cropped up in recent times is we've just been focused on DNA, but now there's RNA editing, there's epigenetic or epigenomic editing. What are your thoughts about that?Jennifer Doudna (13:26):Very exciting as well. It's kind of a parallel strategy. The idea there would be to, rather than making a permanent change in the DNA of a cell, you could change just the genetic output of the cell and or even make a change to DNA that would alter its ability to be expressed and to produce proteins in the cell. So these are strategies that are accessible, again, using CRISPR tools. And the question is now how to use them in ways that will be therapeutically beneficial. Again, topics that are under very active investigation in both academic labs and at companies.Eric Topol (14:13):Yeah. Now speaking of that, this whole idea of rejuvenation, this is Altos. You may I'm sure know my friend here, Juan Carlos Belmonte, who's been pushing on this for some time at Altos now formerly at Salk. And I know you helped advise Altos, but this idea of basically epigenetic, well using the four Yamanaka factors and basically getting cells that go to a state that are rejuvenated and all these animal models that show that it really happens, are you thinking that really could become a therapy in the times ahead in patients for aging or particular ideas that you have of how to use that?Jennifer Doudna (15:02):Well, you mentioned the company Altos. I mean, Altos and a number of other groups are actively investigating this. Not I would say specifically regarding genome editing, although being able to monitor and probably change gene functions that might affect the aging process could be attractive in the future. I think the hard question there is which genes do we tweak and how do we make sure that it's safe? And better than me I mean, that's a very difficult thing to study clinically because it takes time for one thing, and we probably don't have the best models either. So I think there are challenges there for sure. But along the way, I feel very excited about the kind of fundamental knowledge that will come from those studies. And in particular, this question of how tissues rejuvenate I think is absolutely fascinating. And some organisms do this better than others. And so, understanding how that works in organisms that are able to say regrow a limb, I think can be very interesting.Eric Topol (16:10):And that gets me to that recent study. Well, as you well know, there's a company Verve that's working on the familial hypercholesterolemia and using editing with the PCSK9 through the liver and having some initial, at least a dozen patients have been treated. But then this epigenetic study of editing in mice for PCSK9 also showed results. Of course, that's much further behind actually treating patients with base editing. But it's really intriguing that you can do some of these things without having to go through DNA isn't it?Jennifer Doudna (16:51):Amazing, right? Yeah, it's very interesting.Reducing the Cost of Genome EditingEric Topol (16:54):Wild. Now, one of the things of course that people bring up is, well, this is so darn expensive and it's great. It's a science triumph, but then who can get these treatments? And recently in January, you announced a Danaher-IGI Beacon, and maybe you can tell us a bit about that, because again, here's a chance to really markedly reduce the cost, right?Jennifer Doudna (17:25):That's right. That's the vision there. And huge kudos to my colleague Fyodor Urnov, who really spearheaded that effort and leads the team on the IGI side. But the vision there was to partner with a company that has the ability to manufacture molecules in ways that are very, very hard, of course, for academic labs and even for most companies to do. And so the idea was to bring together the best of genome editing technology, the best of clinical medicine, especially focused on rare human diseases. And this is with our partners at UCSF and with the folks in the Danaher team who are experts at downstream issues of manufacturing. And so the hope there is that we can bring those pieces together to create ways of using CRISPR that will be cost effective for patients. And frankly, we'll also create a kind of roadmap for how to do this, how to do this more efficiently. And we're kind of building the plane while we're flying it, if you know what I mean. But we're trying to really work creatively with organizations like the FDA to come up with strategies for clinical trials that will maintain safety, but also speed up the timeline.Eric Topol (18:44):And I think it's really exciting. We need that and I'm on the scientific advisory board of Danaher, a new commitment for me. And when Fyodor presented that recently, I said, wow, this is exciting. We haven't really had a path to how to get these therapies down to a much lower cost. Now, another thing that's exciting that you're involved in, which I think crosses the whole genome editing, the two most important things that I've seen in my lifetime are genome editing and AI, and they also work together. So maybe before we get into AI for drug discovery, how does AI come into play when you're thinking about doing genome editing?Jennifer Doudna (19:34):Well, the thing about CRISPR is that as a tool, it's powerful not only as a one and done kind of an approach, but it's also very powerful genomically, meaning that you can make large libraries of these guide RNAs that allow interrogation of many genes at once. And so that's great on the one hand, but it's also daunting because it generates large collections of data that are difficult to manually inspect. And in some cases, I believe really very, very difficult to analyze in traditional ways. But imagine that we have ways of training models that can look at genetic intersections, ways that genes might be affecting the behavior of not only other genes, but also how a person responds to drugs, how a person responds to their environment and allows us to make predictions about genetic outcomes based on that information. I think that's extremely exciting, and I definitely think that over the next few years we'll see that kind of analysis coming online more and more.Eric Topol (20:45):Yeah, the convergence, I think is going to be, it's already being done now, but it's just going to keep building. Now, Demis Hassabis, who one of the brilliant people in the field of AI leads the whole Google Deep Mind AI efforts now, but he formed after AlphaFold2 behaving to predict proteins, 200 million proteins of the universe. He started a company Isomorphic Labs as a way to accelerate using AI drug discovery. What can you tell us about that?Jennifer Doudna (21:23):It's exciting, isn't it? I'm on the SAB for that company, and I think it's very interesting to see their approach to drug discovery. It's different from what I've been familiar with at other companies because they're really taking a computational lens to this challenge. The idea there is can we actually predict things like the way a small molecule might interact with a particular protein or even how it might interact with a large protein complex. And increasingly because of AlphaFold and programs like that, that allow accurate prediction of structures, it's possible to do that kind of work extremely quickly. A lot of it can be done in silico rather than in the laboratory. And when you do get around to doing experiments in the lab, you can get away with many fewer experiments because you know the right ones to do. Now, will this actually accelerate the rate at which we get to approved therapeutics? I wonder about your opinion about that. I remain unsure.Editing Out Alzheimer's Risk AllelesEric Topol (22:32):Yeah. I mean, we have one great success story so far during the pandemic Baricitinib, a drug that repurposed here, a drug that was for rheumatoid arthritis, found by data mining that have a high prospects for Covid and now saves lives in Covid. So at least that's one down, but we got a lot more here too. But it, it's great that Demis recruited you on the SAB for Isomorphic because it brings in a great mind in a different field. And it goes back to one of the things you mentioned earlier is how can we get some of this genome editing into a pill someday? Wow. Now, one of the things that for personal interest, as an APOE4 carrier, I'm looking to you to fix my APOE4 and give me APOE2. How can I expect to get that done in the near future?Jennifer Doudna (23:30):Oh boy. Okay, we'll have to roll up our sleeves on that one. But it is appealing, isn't it? I think about it too. It's a fascinating idea. Could we get to a point someday where we can use genome editing as a prophylactic, not as a treatment after the fact, but as a way to actually protect ourselves from disease? And the APOE4 example is a really interesting one because there's really good evidence that by changing the type of allele that one has for the APOE gene, you can actually affect a person's likelihood of developing Alzheimer's in later life. But how do we get there? I think one thing to point out is that right now doing genome editing in the brain is, well, it's hard. I mean, it's very hard.Eric Topol (24:18):It a little bit's been done in cerebral spinal fluid to show that you can get the APOE2 switch. But I don't know that I want to sign up for an LP to have that done.Jennifer Doudna (24:30):Not quite yet.Eric Topol (24:31):But someday it's wild. It's totally wild. And that actually gets me back to that program for coronary heart disease and heart attacks, because when you're treating people with familial hypercholesterolemia, this extreme phenotype. Someday and this goes for many of these rare diseases that you and others are working on, it can have much broader applicability if you have a one-off treatment to prevent coronary disease and heart attacks and you might use that for people well beyond those who have an LDL cholesterol that are in the thousands. So that's what I think a lot of people don't realize that this editing potential isn't just for these monogenic and rare diseases. So we just wanted to emphasize that. Well, this has been a kind of wild ride through so much going on in this field. I mean, it is extraordinary. What am I missing that you're excited about?Jennifer Doudna (25:32):Well, we didn't talk about the microbiome. I'll just very briefly mention that one of our latest initiatives at the IGI is editing the microbiome. And you probably know there are more and more connections that are being made between our microbiome and all kinds of health and disease states. So we think that being able to manipulate the microbiome precisely is going to open up another whole opportunity to impact our health.Can Editing Slow the Aging Process?Eric Topol (26:03):Yeah, I should have realized that when I only mentioned two layers of biology, there's another one that's active. Extraordinary, just going back to aging for a second today, there was a really interesting paper from Irv Weissman Stanford, who I'm sure you know and colleagues, where they basically depleted the myeloid stem cells in aged mice. And they rejuvenated the immune system. I mean, it really brought it back to life as a young malice. Now, there probably are ways to do that with editing without having to deplete stem cells. And the thought about other ways to approach the aging process now that we're learning so much about science and about the immune system, which is one of the most complex ones to work in. Do you have ideas about that are already out there that we could influence the aging process, especially for those of us who are getting old?Jennifer Doudna (27:07):We're all on that path, Eric. Well, I guess the way that I think about it is I like to think that genome editing is going to pave the way to make those kinds of fundamental discoveries. I still feel that there's a lot of our genetics that we don't understand. And so, by being able to manipulate genes precisely and increasingly to look at how genes interact with each other, I think one fundamental question it relates to aging actually is why do some of us age at a seemingly faster pace than others? And it must have to do at least in part with our genetic makeup and how we respond to our environment. So I definitely think there are big opportunities there, really in fundamental research initially, but maybe later to actually change those kinds of things.Eric Topol (28:03):Yeah, I'm very impressed in recent times how much the advances are being made at basic science level and experimental models. A lot of promise there. Now, is there anything about this field that you worry about that keeps you up at night that you think, besides, we talked about that we got to get the cost down, we have to bridge health inequities for sure, but is there anything else that you're concerned about right now?Jennifer Doudna (28:33):Well, I think anytime a new technology goes into clinical trials, you worry that things may get out ahead of their skis, and there may be some overreach that happens. I think we haven't really seen that so far in the CRISPR field, which is great. But I guess I remain cautious. I think that we all saw what happened in the field of gene therapy now decades ago, but that really put a poll on that field for a long time. And so, I definitely think that we need to continue to be very cautious as gene editing continues to advance.Eric Topol (29:10):Yeah, no question. I think the momentum now is getting past that point where you would be concerned about known unknowns, if you will, things that going back to the days of the Gelsinger crisis. But it's really extraordinary. I am so thrilled to have this conversation with you and to get a chance to review where the field is and where it's going. I mean, it's exploding with promise and potential well beyond and faster. I mean, it takes a drug 17 years, and you've already gotten this into two treatments. I mean, I'm struck when you were working on this, how you could have thought that within a 10-year time span you'd already have FDA approvals. It's extraordinary.Jennifer Doudna (30:09):Yeah, we hardly dared hope. Of course, we're all thrilled that it went that fast, but I think it would've been hard to imagine it at the time.Eric Topol (30:17):Yeah. Well, when that gets simplified and doesn't require hospitalizations and bone marrow, and then you'll know you're off to the races. But look, what a great start. Phenomenal. So congratulations. I'm so thrilled to have the chance to have this conversation. And obviously we're all going to be following your work because what a beacon of science and progress and changing medicine. So thanks and give my best to my friend there at IGI, Fyodor, who's a character. He's a real character. I love the guy, and he's a good friend.Jennifer Doudna (30:55):I certainly will Eric, and thank you so much. It's been great talking with you.*******************************************************Thanks for listening and/or reading this edition of Ground Truths.I hope you found it as stimulating as I did. Please share if you did!A reminder that all Ground Truths posts (newsletter and podcast( are free without ads. Soon we'll set it up so you can select what type of posts you want to be notified about.If you wish to be a paid subscriber, know that all proceeds are donated to Scripps Research, and thanks for that—it greatly helped fund our summer internship program for 2023 and 2024.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio/video support. 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

In this explainer episode, we've asked Clare Kennedy, Clinical Bioinformatician at Genomics England, to explain what the difference is between DNA and RNA, in less than 10 minutes. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you've got any questions, or have any other topics you'd like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/004-What-is-the-difference-between-DNA-and-RNA.docx  Naimah: What is the difference between DNA and RNA? Today, I'm joined by Clare Kennedy, who's a Clinical Bioinformatician here at Genomics England, who's going to tell us more. So first of all, Clare, what is DNA? Clare: So, DNA stands for deoxyribonucleic acid, and although this is quite a mouthful, DNA is essentially an instruction manual for our body on how to function, and a copy of this manual is stored within almost every cell of the body in a structure called the nucleus. So, our DNA essentially comprises all of the genetic information we inherit from our parents, and this information is contained within two long strands of code, and we inherit one strand of code from our mother and one from our father, and both strands combine and they form a twisted ladder like structure that we call the DNA double helix. So, each strand is made up of small units called nucleotides, and these nucleotides, they differ based on their chemical composition. They can either contain a molecule of adenine, guanine, cytosine or thiamine, and this is why we often see our DNA sequence represented by the letters A, G, C or T. And in total, our entire DNA sequence consists of three billion of these nucleotides. So, as this DNA instruction manual is quite long, it needs to be broken up into smaller sections that the body can read, and that's where genes come in. So, a gene is a segment of the DNA and it contains a particular set of instructions, normally on how to make a protein. So, proteins are essential for life and they're involved in almost every process within our body, and that is why we have around 20,000 protein coding genes in our DNA. Naimah: So then can you tell me, what is RNA and how does this differ from DNA? Clare: So, like DNA, RNA, which stands for ribonucleic acid, is an incredibly important molecule that encodes genetic information, and it's found in all cells of the body. So, RNA consists of only a single strand of nucleotide units, and just like DNA, RNA can be represented by four letters that reflect the chemical composition of each nucleotide. These four letters do differ slightly though, because RNA contains uracil instead of thiamine, so you can distinguish a DNA sequence from an RNA sequence by the presence of the letter U and the absence of the letter T. So, while we think of the DNA as the instruction manual for the body that contains all of our genetic code, RNA is the reader of this instruction manual, and it helps the cell to carry out these instructions, so the proteins can be made. Naimah: So, can you tell me a bit more about this protein production, and how are DNA and RNA involved? Clare: So, protein production all starts in the nucleus with the DNA. So, if we want to make protein, we must first read the portion of the DNA or the gene that contains the instructions to make this protein. So, because DNA is so long, it's really tightly packed into our nucleus, and the region we're interested in might not be accessible, so we first need to open this region out. So, molecules and enzymes help us open this region of the DNA, and once the gene is accessible, they start to read it, and they start to transcribe the instructions that are encoded within the gene into a type of RNA called messenger RNA. So, as the name suggests, messenger RNA is the communicator of the instructions contained within our DNA, and this process is called transcription. So, the messenger RNA then leaves the nucleus and enters the main body of our cell, which is called the cytoplasm, and messenger RNA is transported to the ribosome. Now, the ribosome is a piece of machinery which will build the protein, and it'll use the instructions that are encoded by the messenger RNA. But we need materials to build the protein, and that's where a type of RNA called transfer RNA comes in. So, transfer RNA is instructed to hunt down the building blocks or the amino acids that we need to build the protein, and it brings these back to the ribosome. And then we have a third type of RNA that gets involved called ribosomal RNA. So, ribosomal RNA helps the ribosome assemble these amino acids into proteins in a process known as translation. So, it really is a group effort between the messenger RNA, the transfer RNA and the ribosomal RNA. And once the protein has been assembled, it might go through some more processing steps, and it's eventually exported by the cell to where it's needed. Naimah: Okay, so apart from their roles, are there other key differences between DNA and RNA? Clare: So, as we touched on earlier, the main difference between DNA and RNA is in their structure. So, we have, DNA is in a double stranded helical structure, whereas RNA is single stranded. And because of DNA having this double standard helical structure, it's actually much more stable than RNA, which is more susceptible to degradation by enzymes and other molecules. As DNA contains our genetic code, it's much longer than RNA, and you can only find DNA in the nucleus of the cell as it's much too large to leave the nucleus, whereas you can see RNA in the nucleus and in the cytoplasm. RNA and DNA also differ in the type of code or the lettering they use, so they both use the A, G and C letters in their code, while DNA's is the T lettering and RNA's is the U lettering, and this is due to the differences in the chemical compositions of the nucleotides that make up DNA and RNA. And the nucleotides in DNA also contain different types of sugars from the nucleotides used in RNAs. So, in DNAs, you would have a deoxyribose sugar, whereas an RNA uses a ribose sugar. That's where we get the deoxyribonucleic acid and the ribonucleic acid. Naimah: So Clare, we've talked about the difference between DNA and RNA, but why are these important in clinical care? Clare: So, we can use DNA and RNA to diagnose illness and to also develop therapies against these illnesses. Naimah: Can you give me some examples of where DNA and RNA are used for diagnosing conditions? Clare: Absolutely, so an excellent example is in the diagnosis of cancer. So, the majority of cancers are caused by mistakes in the genetic information encoded within our DNA, and result in the production of malformed proteins. So, we can normally look at the DNA and we can identify certain genetic mutations that cause the cancer. So, examples are breast cancer, ovarian cancers, lung cancers, essentially all types of cancers that you can think of will have genetic mutations associated with them. But then there are cases where no problem with the DNA can be identified, but then when we look at the RNA, we do see a problem. So, a particular example was recently shown in breast and ovarian cancer, where a gene that encodes for a protein called BRCA1 was not shown to have any genetic mutations, however when we looked at the RNA produced from that gene, we could see there are problems with that RNA and essentially identify a genetic cause for that cancer. Naimah: Could you also give me any examples of where RNA or DNA are being used in therapies? Clare: So, absolutely. So, most of us will have heard of RNA vaccines in recent times, such as those that were generated against COVID-19. And essentially how these vaccines work is they deliver small messenger RNA from the virus into the body. The body can then make a protein from this messenger RNA, and the immune system recognises this as an invader and destroys it. So, this low level of viral exposure essentially trains your immune system to respond in the event of an infection, and really the success of the MRNA vaccines against covid has really paved the way for the use of MRNA vaccines against cancer. So, it's believed that we can stimulate an immune response that would destroy a cancer cell using MRNA vaccines, and there are now some studies that are looking at developing messenger RNA vaccines against cervical cancer in particular. So, DNA therapies can actually target genetic mutations and correct them to prevent illness, and one such example is a gene editing treatment that has been developed for the treatment of blood disorders, such as sickle cell anaemia. Naimah: That was Clare Kennedy explaining the difference between DNA and RNA. If you'd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.

Este programa busca facilitar la difusión de la información científica pertinente al área de Neurogenética tanto la aplicable a la vida cotidiana así como aquella del ámbito médico.

Is the human genome highly functional or mostly junk? This is a question that is not only being asked in the creation-evolution debate; it is a question raging in the ivory tower as well. The 'old guard' is much more likely to resist any claim that large swaths of the genome are useful. The 'young punks' in science is more willing to accept the obvious fact that the genome is highly functional. Who is going to win? In this episode, Dr Carter highlights four new studies that ratchet the argument toward high function. Notes and links:' Carter 2023 What proportion of the human genome is actually functional? And how much variation is tolerable? Zhang et al. 2023 FOXP3 recognizes microsatellites and bridges DNA through multimerization Walter 2024 Are non-protein coding RNAs junk or treasure? Stepankiw et al. 2023 The human genome contains over a million autonomous exons Chen et al. 2023 A genomic mutational constraint map using variation in 76,156 human genomes Moran 2023 What's in your genomes? 90% of your genome is junk  

In this episode of the Epigenetics Podcast, we talked with Mitch Guttman from California Institute of Technology about his work on characterising the 3D interactions of the genome using Split-Pool Recognition of Interactions by Tag Extension (SPRITE). Mitch Guttman discusses his exploration of the long non-coding RNA Xist, which plays a crucial role in X chromosome inactivation. He explains how they discovered that Xist is present everywhere in the nucleus, not just in specific locations on the X chromosome. Through their research, they identified critical proteins like SHARP that are involved in X chromosome silencing. The discussion then shifts to SPRITE, a method they developed to map multi-way contacts and generalize beyond DNA to include RNA and proteins. They compare SPRITE to classical proximity ligation methods like Hi-C and discuss how cluster sizes in SPRITE can estimate 3D distances between molecules. The conversation also touches upon the potential of applying SPRITE to single-cell experiments, allowing for the mapping of higher order nucleic acid interactions and tracking the connectivity of DNA fragments in individual cells.   References Jesse M. Engreitz et al., The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science 341,1237973(2013). DOI:10.1126/science.1237973 Chun-Kan Chen et al., Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354, 468-472(2016). DOI: 10.1126/science.aae0047 Quinodoz, S. A., Ollikainen, N., Tabak, B., Palla, A., Schmidt, J. M., Detmar, E., Lai, M. M., Shishkin, A. A., Bhat, P., Takei, Y., Trinh, V., Aznauryan, E., Russell, P., Cheng, C., Jovanovic, M., Chow, A., Cai, L., McDonel, P., Garber, M., & Guttman, M. (2018). Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus. Cell, 174(3), 744-757.e24. https://doi.org/10.1016/j.cell.2018.05.024 Goronzy, I. N., Quinodoz, S. A., Jachowicz, J. W., Ollikainen, N., Bhat, P., & Guttman, M. (2022). Simultaneous mapping of 3D structure and nascent RNAs argues against nuclear compartments that preclude transcription. Cell Reports, 41(9), 111730. https://doi.org/10.1016/j.celrep.2022.111730 Perez, A. A., Goronzy, I. N., Blanco, M. R., Guo, J. K., & Guttman, M. (2023). ChIP-DIP: A multiplexed method for mapping hundreds of proteins to DNA uncovers diverse regulatory elements controlling gene expression [Preprint]. Genomics. https://doi.org/10.1101/2023.12.14.571730   Related Episodes Epigenetics and X-Inactivation (Edith Heard) Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden) Unraveling Mechanisms of Chromosome Formation (Job Dekker)   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

Newly discovered RNAs form a whole new category of the versatile biomolecule RNA.  These "new" RNAs are tiny relative to the RNAs already characterized.  Nicknamed, miRNA, siRNA and piwiRNA, they are involved in regulating a host of cellular functions and even pass on hereditary traits.

“The history of science, it turns out, is filled with stories of very smart people laughing at good ideas.”—Katalin Karikó Ground Truths podcasts are now available on Apple and Spotify!The list of obstacles that Kati Karikó faced to become a scientist, to make any meaningful discovery, to prevail over certain scientists and administrators who oppressed her, unable to obtain grants, her seminal paper rejected by all of the top-tier journals, demoted and dismissed, but ultimately to be awarded the 2023 Nobel Prize with Drew Weissman, is a story for the ages. We covered them in this conversation, which for me will be unforgettable, and hopefully for you an inspiration.Recorded 30 January 2023, unedited transcript belowEric Topol (00:06):Well, hello, this is Eric Topol with Ground Truths, and I am really thrilled to have with me Kati Kariko, who I think everyone knows won the Nobel Prize with the Drew Weissman in 2023 and she has written a sensational book, it's called Breaking Through. I love that title because it's a play on words, a breakthrough and breaking through, and we have a lot to talk about Kati, so welcome.Katalin Kariko (00:34):Thank you very much for inviting me.Eric Topol (00:36):Yes, well I'd like to start off, as you did in the book with your background in Hungary where of course you started with a tough background in a one room house without running water and you never had exposures to scientists and somehow or other you became interested in science and you attributed some of these things like your biology teacher, Mr. Tóth and the book Stress of Life [by Hans Selye] Could you tell us a little bit more what stimulated you in a career of science?Katalin Kariko (01:18):I have to say that every child is interested in understanding the nature around them and so I was surrounded with nature because we had big garden, we had animals around and it was an exciting thing. The children ask questions and if they try to find an answer and teachers or parents might give the answer, but definitely the school, even elementary school was very stimulating. Teachers, chemistry teacher, figure out how we can make crystals and I was so excited to have my own crystals and things like that and in high school the teachers were so engaging and not like they tried to put all of the information into your brain, but they encourage you to think yourself, so that's all contributed. I think that most of the child in the first, I don't know, six, seven years of their life that's how they can see their parents behaving, their friends, the school, classmates, and they shaped what kind of people they will be at the end and the rest of it is refining.Eric Topol (02:41):Right, right. Well one of the things I loved that you brought up in the book was how much you liked the TV show Columbo. That's one of my favorite TV shows of all time and one more thing, one more thing. Can you talk a little bit about Columbo? Because in some ways you were like the Peter Falk of mRNA in terms of one more thing.Katalin Kariko (03:09):Yes, so I realized that we as researchers, we are not called searchers, we researchers, so we are repeating things. Of course everybody knows who committed the crime in Columbo because this is how it starts and you don't have to figure out, but it seems always that things in a different direction you would lead but all the little clues and some of my colleagues said that they as a physician, they have this tunnel vision. So the patient comes and they can figure out probably from some clues that this is the disease and they get back the lab results and others. Then they realize that one or two things is not fitting, but they always so strongly believe their first instinct. What I taught them to focus on those which will not fit because that will lead to the real perpetrator in case of Columbo.(04:23):And so I like the simplicity. I know that what we are doing this research is very over complicated, but we can break down in very simple question, yes or no and then repeating things and many experiments. When I did one was the experiments really the question and the nine of them was like just controls always. I have to have a control for that, control for that and since I work most of the time with my own hands myself, so I had to make sure that I think through that what will be the experimental outcome and then think about that. Do I have a control for that? So that many times in my brain before I performed the experiment in my brain, I predicted that what will be the outcome, of course you never get the outcome what you expect, but at least you have the control that you can exclude a couple of things and so this is how I function usually in the end of the 20th century, 21st century people did not work like I did alone most of the time.Eric Topol (05:35):No, I see how you described it in the book was just so extraordinary and it really was in keeping with this relentless interrogation and that's what I want to get into is particularly the time when you came to the United States in 1985 and the labs that you worked in predominantly in Philadelphia through that period before leaving Penn to go on to BioNTech. So, you first kind of beached in at Temple University with a monster at least as you portray him in the book. I mean it was nice that he picked you up at the airport, you and your family. How do you say his name? Suhadolnik.Eric Topol (06:31):But not only was the lab kind of infested with cockroaches, but also after working there for a number of years, a few years, you then had gotten an offer to go to Johns Hopkins and when you informed him about that he threatened and did everything he could to ruin your career and get you deported. I mean this was just awful. How did you get through that?Katalin Kariko (06:58):As I mentioned later on, I went back and gave a lecture there and I have to say that I always put positivity in forefront, so I learned a lot from him, and he invited me to America. I was always very grateful, and he was kind, and we did very well, and we did a lot of publication. In one issue of biochemistry, we had three papers and two of them I was the first author, so I worked very hard and so he liked that, and he wanted me to stay there. I just learned that from this Selye book that this is what is given and then what I can do, I cannot change him. I cannot change the situation, how I can get out from it and that's what I focused on, so I am not bitter about him. I liked him and the same for other people. When I get an award, I usually thanks to all of these people who try to make my life miserable. They made me work harder.Eric Topol (08:05):Well, but you were very kind like you said when you went back to Temple many years later to give the lecture because what he did to you, I mean he was so vindictive about you potentially leaving his lab, which he demanded that he be called the boss and he was going to basically, he ruined the Johns Hopkins job. He called them and you were so nice and kind when you went back to give the lecture without saying a negative word about him, so I give you credit, when somebody goes low, you went high, which is nice.Katalin Kariko (08:40):It is important, which I learned from the Selye book, that you don't carry any grudge against anybody because it'll poison you and as Selye also said that when you are very frustrated and very upset, the quickest way you can think about how you can release the stress is revenge. He said, don't do that. It escalate. It hit you back. You have to think about how you can be grateful for the same person you were just ready to take some revenge and that's what you have to practice. Sometimes it is difficult to feel that, but I don't have any bad feeling against my chairman who put my stuff on the hallway.Eric Topol (09:24):Oh yeah, I was going to get to that. So then after a short stint at the Uniformed University of Health Science where you had to drive three hours from Philadelphia to go there and you would sleep on the floor. I mean, I have to say Kati, if I was driving three hours, all I'd be thinking about is how desperate situation I was put in by the prior PI you work with. Any rate, you work there and then finally you got a job with my friend Elliot Barnathan, a cardiologist at University of Pennsylvania. So here you are, you're very interested in mRNA and you hook up with Elliot who's interested in plasminogen activators, and you work in his lab and it's quite a story where one of the students in his lab, David Langer, ratted on you for being blunt about the experiments getting screwed up and then later you wind up working in his lab. Tell me a bit about the times with Elliot because he's a very gracious, I think he was very supportive of your efforts and you got him stimulated about the potential for mRNA, it seems like.Katalin Kariko (10:41):Yes, so I was desperate to be away from my family at Bethesda and try to get back and every day I sent out several applications. This was in 1989, so you had to send letters and then I called up usually the secretaries about what's going on and I called up also a secretary and she said that they were advertised because nobody was good enough. I said, can you ask him to look at again my application? Then half an hour later, Elliot called me back that come and bring your notebook. He wanted to know what kind of experiment I am doing, and he opened when I came a couple of days later and pulled up a northern blot and he said, you have done that? I said, yes, I did. He said, okay, you are hired and so that, because Elliot is just a couple of days younger than me, I convinced him that we should do kind of mRNA research and he agreed, and we did several experiments and he helped me to get all of these experiments ongoing and so it was a very exciting time and I listened. Elliot was there in many awards ceremony including the Nobel Prize. He was my guest because I was very grateful to him because I have to say that he tried to protect me and he get trouble for that because in higher up and when he was looking for tenure, somehow he get R01, several of them, but they did not put him tenure because he was standing up for me and he paid the price.Eric Topol (12:42):Do you think the reason in part that he went to Centocor, a biotech company who I worked with quite extensively was because he stood up for you?Katalin Kariko (12:54):He mentioned to the chairman that he's waiting for whether he will be tenured because he has a job offer with ReoPro what he was doing there in the lab and testing out and the chairman told him that, take that job.Eric Topol (13:11):Yeah. Well, that's interesting. I know Judy Swain very well, and she did everything she could to hurt your career. She demoted you, or actually she wanted you to leave, but you wound up taking a demotion and also Bill Kelley, who I know well, he was the Dean and CEO of the UPenn. Did he ever get any direct involvement with, because much later on he was advocating for your recognition, but during that time, he could have told Judy Swain to stop this, but did he ever get involved, do you know?Katalin Kariko (13:45):I was very low level of nobody, so he would not. It was interesting, we were hired on the same day in 1989. I was first, and I met him, Bill Kelley when the new faculty was hired, and I was so happy because my first project in Hungary was Lesch-Nyhan syndrome, and I know that he discovered the gene, and I was looking up to him very much always.Eric Topol (14:15):Well, you said in the book you were over the moon and I have to say, I worked with him. My first job was at University of Michigan, and I worked with him for six years before he left to go to Penn, and we've been friends all these years, but what happened with Judy Swain, as I read in the book, I got all it bristled. I really was upset to read about that. Anyway, somehow you stayed on, Elliot moved, by the way, during that time with Elliot, you were able to get mRNA to make urokinase plasminogen activator (uPA), and that was a step in the right direction. Before we leave, Elliot, if you had stayed there, if he had gotten tenure, do you think you would've ultimately together made the discovery that you did with Drew Weissman?Katalin Kariko (15:05):I couldn't be tenured because it is a clinical department and I had a PhD and nobody at the clinical department can be, but I could have been research associate professor if I can get a grant and in 1993, I already had submitted grant on circular RNA. When people in these days, they say that, oh, that's a novelty. Oh, in 1994, 1995, I had several grants on circular RNA I submitted for therapeutic purposes, and Elliot helped me with English and computer, everything what he could, but it is important that he was not an immunologist and I needed discovery. When I work with him, I did not realize the mRNA was inflammatory.Eric Topol (16:02):Right, right, exactly. We're going to get to that in a minute. Now, after Elliot left, then you needed someone else to support you, and you wound up with, as I mentioned earlier, David Langer, a neurosurgeon who you previously knew, and he also stood up for you, right?Katalin Kariko (16:18):Yes, yes. So at the beginning, every lab, when you have a medical student, they kind of know everything. One day he just told me that, Kati, I will want to learn everything you know, and I will know everything you know. I said, oh, by that time while you are learning, I learned so much more, you never catch me. That always I had to put him back, but kind of he liked how I worked, I concentrate, I didn't chitchat. Then he was just keep coming back when I was working, even with Elliot and he advanced from medical student to residency and so on, and then when he learned that I have no job because Elliot is leaving, then he went to a Eugene Flamm, the chairman of neurosurgery, and he convinced him that neurosurgery needs molecular biologics. That's what he was arguing and thanks to David and the chairman Eugene Flamm, then for 17 years I had a laboratory, and I had a financial support. Not much.Eric Topol (17:36):Yeah, I mean that was great, but again, you were not getting any real support from the university and then all of a sudden you show up one day and Sean has all your lab, everything that you worked on thrown in the hallway. I mean, that's just incredible story, right? At any rate, you then wound up because you were basically hawking mRNA as a path of science. It's going to be important. By the way, my favorite quote in the book, Kati. The history of science it turns out is filled with stories of very smart people laughing at good ideas. I just love that quote and it kind of exemplifies your career and your success, but you were steadfast and you ran in, of course, the famous story to Drew Weissman at the Xerox machine, and you were hawking trying to get anybody to believe it as you called it, led to the mRNA Believers Club, which only a handful of people in the world ever got there.(18:38):And here you have you take on something that obviously 1960 in your lifetime, early in your lifetime it was discovered, but everyone knew it was unstable, very difficult to work with, very challenging. Of course, you realized that could be beneficial, but you hooked up with Drew the immunologist that you mentioned, and I didn't know by the way, he had type one diabetes. I learned that from your book, and both of you worked so hard and it's just really incredible, but while you're at Penn, the famous or infamous Jesse Gelsinger case and his death occurred and he had the cytokine release syndrome, and you learned from that, right?Katalin Kariko (19:25):Yes. By that time, we also could see that the RNA could be inflammatory, but in his case, of course, because the virus was causing it or what certain condition caused that. I have to say that, people work at gene therapy at Penn and mostly of viral programs. When I mentioned I tried to make gene therapy with mRNA, of course everybody felt sorry for me. Poor Kati, hate RNA, it always degrade, but I have to say the degradation is coming mostly because the molecular biology laboratory, they use plasmid, and when they isolate plasmid, like the QIAGEN kit, they start with the RNAs. They add RNAs because you have to eliminate the bacterial RNA, and they contaminate the whole laboratory, the refrigerator door, the gel opera, everybody's RNAs and so that's what extra problem with working with RNA. So I could make RNA, and so it was working and kind of try to express that and I made a lot of RNA for people probably they still have in their freezer, never tested because I was a pusher.Eric Topol (20:52):Yeah, yeah. Well, what was fascinating of course is you had already learned in mice about this inflammation from putting mRNA in vivo, and then you made the remarkable discovery, which was the paper in Immunity that had been rejected by Nature and many other papers, even though you had been told if you could get a paper in Nature, maybe that could help your career, right. Back in 2021, the journal of Immunity, a very highly regarded self pressed journal, they asked me to comment on your discovery and I wrote, you may have seen it. Of course, several people wrote Tony Fauci and others. What I wrote was what began as a replacement for a uridine base to squash an inflammatory response in mice evolved into the basis for a broad therapeutic platform to fight both communicable and non-communicable diseases in people. So, this discovery that you made in that classic 2005 paper, which is the most important paper ever published in the journal Immunity, was the Toll-like receptor was mediating the inflammation.(22:05):And if you change the uridine to pseudouridine, you could essentially blunt or block the inflammation. This was a seminal discovery that opened up mRNA, but not just for Covid of course, but for so many pathogens and as we'll talk about when we wrap up about all these other things. So when you did this paper and Drew said when it's published, the phones are going to be ring off the hook and no one even acknowledged the paper, right? I mean no one realized how this was one of the most important discoveries in the history of biomedicine, right?Katalin Kariko (22:43):Yes. Especially knowing that Drew is not the person who is exaggerating things. Drew is very modest and would not say such things. I am more like daughter, maybe this happened, but he is not like that and I got the one invitation to go to the Rockefeller University for a meeting, and then I went to Japan from 2005 and it was 2006. Both of them that was invitation, and nothing happened in 2007, 2008 and 2009.Eric Topol (23:24):But those meetings that you went to, they were kind of obscure like microcosm groups. I mean they were relevant to your work, but they didn't realize this is a big deal. I mean, this is like a world changing type of finding because now you could deliver things in cells. Now of course, you worked on this for three decades and the people that think that you can do a flash in the pan science, but at the same time nanoparticles separately were being pursued. How important were the nanoparticles to make for the package for the ultimate success? When Covid hit in late 2019 and now you had been working at BioNTech, how would you rate the importance of the nanoparticles in the story?Katalin Kariko (24:23):For the vaccine it definitely is important because everybody ask the mRNA, if not immunogenic, where do you have the adjuvant? Where is the adjuvant? Then lipid nanoparticle contains an ionizable lipid, which was the adjuvant and why it is important that not the mRNA was inducing the response because the mRNA induced interferon, and if you have interferon, then follicular T-helper cells is not form, and then you get very low amount of antibodies, but if you do not induce interferon, but you induce IS6 and other cytokines is beneficial to have high level of antibodies, so that's what the ionizable lipid was causing and that's the adjuvant in the lipid nanoparticle. Yes, I always emphasize that it is very important and of course when we use the particle that was totalization, then it did not contain ionizable lipid.Eric Topol (25:24):Right? I think that's where there's a misconception because of the Nobel Prize recognition last year, a lot of people think, well, that's all tied only to the Covid vaccine. Actually no, your discovery was much bigger than that and it was applied for the Covid vaccine of course with the nanoparticle package, but yours is as we'll get to in a moment, much, much bigger. You left Penn, that was in 2013, and then you spent several years in Mainz, Germany working with the folks at BioNTech, and you really enjoyed that and they appreciated you then as opposed to what you dealt with at Penn where it was just that you kept hearing about the dollars per net square footage and all these ridiculous things and just extraordinary to go back there. Now I just want to mention about your own gene transfer, your daughter. Your daughter is a two-time gold medal Olympiad in rowing, which is incredible. So she didn't go down the path of science, but she also became a world leader in a field. Is that transmitted on a particular chromosome in the family?Katalin Kariko (26:54):I think that she just could see that you have to focus on something and then you give up many things and you focus and then achieve, and then you get the new goal, set up a new goal. I mean she get somewhat articulated at Penn, she get a master in science and later in UCLA, she get a MBA degree, but 10 years she was like, for me, it is a very boring thing, just rowing going backwards. Isn't that boring every day? She said, no, mom, it is fun. Every practice is different, I enjoy. The minute I don't enjoy, I will stop doing it.Eric Topol (27:36):Yeah. Well it's amazing story about Susan and of course the expansion of your family with a grandchild and everything else that you wrote about in the book. So now let's go to this story, the big story here, which is mRNA. Now you can get into cells, you can deliver just about anything. So now it can be used for genome editing, it can be used for all these different pathogens as vaccines and including not just pathogens but potentially obviously cancer, to rev up the immune system, neurodegenerative disease to prevent these processes and potentially even preventing cancer in a few years ahead. How do you see this platform evolving in the years ahead? You already have seen many vaccines getting approval or under intense study for pathogens, but that just seems like the beginning, right?Katalin Kariko (28:38):Yes, yes. When I came to Penn, the major advantage was going to lectures and when I went to the lectures, I always at the end of it think, mRNA would be good for it. So, I was collecting all of these different fields and then what happens is right now I can see the companies are making those RNA, which I thought that it will be useful and even many, many more things that they are applying and now it is up to those specialists to figure out they don't need me. They need experts on cardiology and other fields and allergies. There is also to tolerate allergies and there are so many fields scientists will be figuring out there what is useful for the mRNA, and they can just order now or create their own RNA and test it out.Eric Topol (29:38):It's actually pretty amazing because I don't know where we'd be right now if you had not been pushing this against all adversity. I mean just being suppressed and being told, put your stuff out in the hallway or being thrown out of the university and not being able to get any grants, which is amazing throughout all this time, not being able to get grants, it tells a big story and that's why the book is so sensational because it's obviously your autobiography, but it tells a story that is so important. It goes back to that memorable quote that I mentioned. You wrap up the book with your message of your life story, and I do want to read a bit of that and then get your reaction. My first message is this, we can do better. I believe we can improve how science has done at academic research institutions.(30:38):For one thing, we might create a clearer distinction between markers of prestige, titles, publication records, number of citations, grant funding, committee appointments, etiquette, dollars per net square footage, and those of quality science. Too often we conflate the two as if there's one in the same, but a person isn't a better scientist because she publishes more or first perhaps, she's holding back from publication because she wants to be absolutely certain of her data. Similarly, the number of citations might have little to do with the value of the paper and more to do with external events. When Drew and I published our landmark Immunity paper and indeed it was, it barely got any notice. It took a pandemic for the world to understand what we've done and why it mattered. I mean, that's profound, Kati, profound.Katalin Kariko (31:42):I have to tell you that what I could see as the science progress. Every scientist starts with understanding something to help the world but somehow they publish because they have something to say, but somehow, it's shifted. Now we want more money, more people would come, those people had to get publication because otherwise they cannot graduate. They need first to author a paper. They publish even when it is not finished or have nothing to say and then somehow the focus is promotion. You are advancing your position, and the tool is doing the experiments. If you see I was demoted, I was pushed out so if my goal would have been to see that I am advancing, then I would give up because that's what the problem is. So that focus is going away from the original thing that we want to understand the science because if you want to understand the science, you are even happy when you can see a publication doing half of that you have done already because you say, I wanted to understand, here's a paper they did, similar thing I did, but the people think, oh my god, my journal paper is out and my promotion is out because they discovered and they published before me, so that's the problem.Eric Topol (33:12):Well, I mean if I made a list of all the adversity that you faced from growing up in the Russian communist run Hungary to coming to the US not even knowing the language and also all the sacrifices you made along the way with your family and when you would go to Bethesda or when you moved to Mainz or I mean all along the whole time, no less what the university of Temple or Penn. I mean the list is very long and somehow you prevailed above all that, which is just so startling but another thing I want to just get into briefly, as you know, this has been a shocking counter movement to the vaccines and giving ridiculously the mRNA as a bad name. In the book, you kind of had a way to foreshadow this because back in the 1968 pandemic that you obviously experienced, here you talked about that.(34:30):You said we restricted our movement, limiting our contact with others. We scrubbed, we disinfected. I suppose the party encouraged this, but nobody complained about government overreach. This was a virus. It had no ideology, no political agenda. If we weren't careful, it would spread, then we would all suffer. These were just the facts. That's how viruses work. So how come we still don't know that? That was 1968 in Hungary and here we're go in the United States, and we have a huge movement, anti-vaccine, anti mRNA, Covid vaccines, and it's very worrisome because all the great science is threatened by this misinformation and disinformation. What are your thoughts about that?Katalin Kariko (35:27):Yes, I heard that viruses, they love democrats because everybody can do whatever they want, whereas in other countries give an order, everybody has to have vaccine and then that's different, but yes, I understand that the novelty the people were always against, even when X-ray was introduced, people thought that people will look through my clothes and seeing me naked because they take part of the truth and they don't say, maybe through the flesh is going through and I can see somebody's bone or something. Then they distort, and they create a fear and if you make fear, then you can control like Lord of the Flies, somebody you are afraid of and then you can control and you can be afraid of the virus or you can be afraid of the vaccine. Then that's what I don't understand exactly true said that when they investigated those who are spreading most of these news about against the vaccine is they are selling some kind of products benefiting just like a hundred years ago, those who were afraid that they can see through their clothes some they start to sell X-ray resistant underwear.(36:57):Of course people, they made money on the people's fear. I don't know that's how to fight it or I think that the honesty when the scientists would say that, listen, we don't know today how it spread. This is how we suggest, be afraid, wash everything. Oh no, we know that it is in the air so that okay, you don't have to wash your clothes when you go out and come back but don't go to crowded places. In politics it's not working because it is like wishy-washy. Yesterday you said something and today, because we learn, they have to understand this is a science process constantly correcting. In politician, I know everything, this is how to do, they want to reflect this confidence. That's what it is and that's why politics everywhere mixed up with this. Some leaders want to reflect this confidence and they do things which helps the virus to spread.Eric Topol (38:11):Right. Well, I'm glad to get your perspective because obviously when you work so hard throughout your career and then you see the backlash, that's unwarranted. It's always good to be circumspect of course, but to say that this was done in a flash in the pan and it's never really, it's gene therapy and it's changing your DNA, I mean it's a lot of crazy things that of course that you brought out in the book as well. Now before wrapping up, you wrote the book before you were awarded the Nobel Prize and this recognition, you and Drew of course became fantastic, so richly deserved, but many things occurred and I wanted to ask you. For example, you did your PhD and your postdoc at the University of Szeged in Hungary, and you went back there, and I think you were celebrated in your university, perhaps the first Nobel laureate. I don't know, I would imagine perhaps. The second, oh okay but also the last thing that was recognized in the book it was a much different thing. It was like the Time 100 recognition but now that you have had many of these unanticipated awards, what are your thoughts about that? I mean, it is wonderful to get recognized by the university that you trained and the people that you grew up with.(39:53):Has this changed your life or is it really very much the same as it was?Katalin Kariko (40:00):My life is very much the same as it was. I am living in the same house. We moved in 1989 and okay, last year I get a new car. Up until then, I never had, only just some beat-up, last year I purchased my first new car but that's luxury when you are 68 years old, you could afford. Everything was a surprise because 40 years I never get any award and the first award I get in 2021. I tried to articulate to more people, life as a scientist is similar to mine. They are immigrant, they are not recognized and I try to tell them just not to focus something like the university is not grateful. Who is the university? Just they are walls. What administrator would tap your shoulder. You have to know that what you are doing is important and if you get pushed around, you always have to do what Selye said, figure out what you can do. Always that, not what they should do. The agency should give me the money, the boss, the superior should help me. No, I cannot make other people to do. I have to figure out what I can do. I can write better and better and rewrite, generate more data for a submitted grant application and always, that's why all of these naysayers made me better because I'm not focused on revenge or anger, but always, how can I be better.Eric Topol (41:53):So that gets me to what you do next. I know you're an avid reader. I know you read so much about science and your field and broader of course I take it you still are doing that, but what's in the next chapter for you? I can't imagine you're ever going to rest.Katalin Kariko (42:16):No, no. I will be six feet under when I can rest, I realize now. It is just that you are on a different field, and you understand like nucleotides, how naturally you make RNA, what is the transporters, what is happening in the mitochondria, different things that iron sulfur clusters and then you start to investigate like three months I was just reading one topic. I didn't even know about it or how in my life I was reading so many things. I realized there are so many diseases, I understand what is the reason, people don't. When I was at Penn I went to different people, professors about my idea for certain diseases but I was nobody and nobody listened. Now, I'm somebody. I have to be very careful because I say a name of the disease people will line up here and say, don't talk to Eric. Go and do something, help us and so that's what I try to help. I think that I understand certain disease, which is so enigmatic and nobody has a clue and maybe I have a solution for that. That's what I try to do now.Eric Topol (43:38):Do you ever go to Penn? Do you ever go to work in there?Katalin Kariko (43:44):No, I don't. When you are forced to retire, and I knew that they would throw me out because it was 2012, right before Christmas I was told that get out because you didn't get the 2012. Last time I submitted an mRNA for stroke therapy. Still very valid and good idea but anyway, I knew that I will be pushed out, but I don't have grudge, even the chairman. How can I expect the neurosurgeon who is doing the operation he just can see that I did not get the funding and those people who make the decision that my proposal is not good, they are expert. He's not an expert. He just can see that this is what the expert said. I talk to him, I don't blame anything.Eric Topol (44:37):Good for you. I mean I think it's much easier to be vindictive and you have to have the philosophy that you have, which is not to hold any grudges after all that has basically been done to you by many people along the way and I think we've covered that. I know this is a very different interview perhaps than many others that you've had. I didn't bring up the teddy bear and I didn't bring up a lot of things that others have brought up because they've already been covered. I wanted to get into what you had to endure, what you had to do to persevere and how it has changed the life science and medicine forever and now, still today, the mRNA package will be improved. I mean we've already learned, for example, the change of the two proline substitution that Andrew Ward at my place, along with Jason McLellan and others to make it to better immune response. It can be improved with a 6-P proline substitution. We can beat nature just like you did with the uridine substitution and the nanoparticles will improve and this whole package has got an incredible future but it's thanks to you, if it induced massive inflammation, it never would've been possible.Katalin Kariko (46:02):Yes, I always said that hundreds and thousands of scientists, every time I thanks them, those people, even not with us, I was reading their papers and it all contributed to this development and learning. So, I am not thinking that I was many, many other people together, we did that.Eric Topol (46:30):Well, I am so indebted to you as everyone who understands sciences, and it's of course a bigger story than mRNA. It's what you endured and how you persevered and against all odds, I mean truly against all odds, so thank you. Did I miss anything that I should have asked you about?Katalin Kariko (46:51):No. I have to say the book came out and now I can see in different social media that how other scientists get inspired. There was one who said that she quit doing PhD and she read my book and she cried, she laughed, and she went back. She realized that there is more to it because so many is expecting to do some work and then there will be some rewards. The rewards is this is not a short distance. This is a marathon to be scientist and you have to see the goals and it will one day and you might not the one that cross first the finish line, but you are helping others. That's what is important and that's what I am glad that I work with this and write this book so that other scientists more can associate because they feel the same way, that they are not appreciated. Things are not going as expected and then they might be inspired not to give up and that's what is also an important message.Eric Topol (48:11):Well, that's why I love the book because it is so inspirational and it will make people cry. It will make people commit to science or appreciate it more than ever. I don't know if you saw it, but I put it as my 10 favorite books for 2023 and indeed, I could have been the most favorite in many respects. So I hope more people listening or watching the video will read the book because it has a lot. I'm so glad you wrote it, Kati, because if we only knew you from papers and Nobel Prize, you wouldn't know the true story. We wouldn't know really what your life has been like over these many decades. So, thank you for that as well and thank you from the life science, the medical community, and for everyone, for all that you've done to change the future and the current state of medicine.Katalin Kariko (49:10):Yeah, thank you very much asking and I might add to the book that the book is published in many different languages is coming Italian and French, German, Thai, Japanese, Chinese. So scientists all over the world can read their native language and maybe they will be inspired.Eric Topol (49:28):Oh, I have no question about that. It's a story that it should be a movie so that the people that won't read the book will hopefully watch the movie. Has there already been a plan for that?Katalin Kariko (49:40):There was, but I don't think that you know they have this strike during the summer, and I don't know where it ends.Eric Topol (49:52):I wouldn't be surprised if it gets done in the future and I hope they'll consult with you, not just read the book and it'll be interesting who they get to play you in the movie, but thank you so much, Kati. What a joy and I look forward to future visits with you. Get full access to Ground Truths at erictopol.substack.com/subscribe

Catching cancer at its earliest stages saves lives. But in a body made up of trillions of cells, how do you spot a small group of rogue cancer cells? Biomedical researcher Hani Goodarzi discusses his lab's discovery of a new class of RNAs that, when paired with emerging AI tools, could help detect cancer earlier, more precisely and even through routine blood work — potentially transforming our understanding of the disease.

Catching cancer at its earliest stages saves lives. But in a body made up of trillions of cells, how do you spot a small group of rogue cancer cells? Biomedical researcher Hani Goodarzi discusses his lab's discovery of a new class of RNAs that, when paired with emerging AI tools, could help detect cancer earlier, more precisely and even through routine blood work — potentially transforming our understanding of the disease.

Catching cancer at its earliest stages saves lives. But in a body made up of trillions of cells, how do you spot a small group of rogue cancer cells? Biomedical researcher Hani Goodarzi discusses his lab's discovery of a new class of RNAs that, when paired with emerging AI tools, could help detect cancer earlier, more precisely and even through routine blood work — potentially transforming our understanding of the disease.

New research has expanded our understanding of the function of DNA that once was thought to be "junk DNA."  Newly discovered RNA molecules are involved in the regulation of the cell in ways we never could have imagined.

Nytt år och nya loppmöjligheter. Men hur lägger man upp säsongen på bästa sätt för att kunna prestera bra lopp? Andreas Almgren, som går in i ett OS-år, vet allt om hur man ska sätta tävlingsschemat för att få till formtoppar för de viktigaste loppen. När ska man använda tävlingar som ett led i träningen, hur många tävlingar kan man vara i toppform för och måste man dra ned träningen för varje tävling? Andreas har svaren. Inte nog med att han hjälper oss med våra tävlingsfunderingar så aviserar han två väldigt intressanta starter på landsväg i början på säsongen. Gör ni inte redan det, så följ Andreas på Strava där han lägger upp mycket av sin träning.  Andreas Strava Manne förbereder sig för resa till Thailand med lite extra kryddade pass och John laddar för årets första (och sista) tävling. De sammanfattar dessutom sina år och aviserar sina mål för 2024.  Veckans Sponsor: Petzl         

Chromosomal recombination is an essential part of the life cycle of all sexually reproducing organisms. Yet, the system is complex, involving hundreds to thousands of proteins and RNAs. It also involves DNA repair pathways, which are themselves incredibly complex. The newest available information on recombination tells us it is mutagenic, meaning that recombination erodes the very places where recombination happens. How did such a system arise by chance? Can we assume the recombination rate has always been the same? What happens when a new allele arises in the protein that controls recombination? What is the mutation burden caused by this important system? Finally, how does this affect the creation-evolution debate? Links and notes: 15 Questions for evolutionists, #8 How did sex originate? Geeking out about DNA damage repair, June 2023. Grey et al. 2018 PRDM9, a driver of the genetic map, PLoS Genet 14(8):e1007479. Altemose et al. 2017 A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis, eLife 6:e28383. Robert Carter gets everything wrong?, creation.com, 10 Jul 2021. Hussin et al. 2011 Age-dependent recombination rates in human pedigrees, PloS Genetics 7(9):e1002251. Wang et al. 2012 Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm, Cell 150(2):402–12. African origins and the rise of carnivory, creation.com,19 Dec 2020. Hinch, A.G. et al., The landscape of recombination in African Americans, Nature 476:170–177, 2011. Hinch et al. 2023 Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line, Science 382:eadh2531.

Priests and Priestesses come in a variety of forms: suits, dresses, military fatigues, white lab coats, etc. They walk on red carpets, appear on the silver screen, live in the White House, and work at the pentagon pentagram. Their departments of entertainment, defense, health, and the like are really those of propaganda, war, and death.One of the greatest illusions, and allusions, or magical spells, used by these magi are the countless predictions, projections, and rhetoric about this or that: gene editing, climate, disease, death, reproductive research, etc. Turns out, most, if not all, are conducted through computer model simulations of the real world. Science Daily reports that Quantum Biology and AI are being merged by Oak Ridge National Lab, but the research is not so realistic: “Existing models to computationally predict effective guide RNAs for CRISPR tools were built on data from only a few model species, with weak, inconsistent efficiency when applied to microbes.”Climate records this year have also been reached through the same means. The University of Maine's Climate Reanalyzer uses satellite data and computer simulations to measure the world's condition….The AP goes on to say “NOAA, whose figures are considered the gold standard in climate data, said in a statement… that it cannot validate the unofficial numbers. It noted that the reanalyzer uses model output data, which it called “not suitable” as substitutes for actual temperatures and climate records.”Pfizer said the same thing earlier this year about their work: “With a naturally evolving virus, it is important to routinely assess the activity of an antiviral. Most of this work is conducted using computer simulations or mutations of the main protease–a non-infectious part of the virusA Lancet study from 2021 acknowledged the same: “Early projections of the COVID-19 pandemic prompted federal governments to action. One critical report, published on March 16, 2020, received international attention when it predicted 2 200 000 deaths in the USA and 510 000 deaths in the UK without some kind of coordinated pandemic response.1 This information became foundational in decisions to implement physical distancing and adherence to other public health measures because it established the upper boundary for any worst-case scenarios.”This show is part of the Spreaker Prime Network, if you are interested in advertising on this podcast, contact us at https://www.spreaker.com/show/5328407/advertisement

Dr. Roger Foo is the Zayed bin Sultan Al Nahyan Professor of Medicine and Head of the Cardiovascular Research Institute at the National University of Singapore. His lab investigates the molecular mechanisms that regulate cardiac biology and disease. He talks about the genetics of heart disease and the roles of circular RNAs.

Francesco Loria is a Ph.D. student in biomedical science at the Swiss Laboratory for Doping Analysis in Lausanne and the University of Geneva. In this episode, we hear more about Francesco's career, his research on the potential for reticulocyte-related RNA to be used as biomarkers to detect blood doping, and his receipt of one of this year's PCC-sponsored Anti-doping Predoctoral Awards in partnership with the American Physiological Society (APS).

RNA Interference, known as RNAi, is a biological process that leads to the silencing of gene expression.  A lot of plant viruses are RNA viruses including grapevine leafroll-associated virus and grapevine red blotch virus. Yen-Wen Kuo, Assistant Project Scientist in the Department of Plant Pathology at the University of California, Davis is researching ways to induce RNAi in grapevines to target virus. Growers may have heard of double-stranded RNA sprays which are intended to initiate RNAi. The challenge has been that double-stranded RNA breaks down quickly in the elements. The Kou lab is working to improve this process and look for alternatives that will have little impact on the ecology. Resources: 71: New Techniques to Detect Grapevine Leafroll Disease 131: Virus Detection in Grapevines Abstract: Development of Agrobacterium tumefaciens Infiltration of Infectious Clones of Grapevine Geminivirus A Directly into Greenhouse-Grown Grapevine and Nicotiana benthamiana Plants Kuo Laboratory – Plant Virology Maher Al Rwahnih, Foundation plant services RNA-Based Vaccination of Plants for Control of Viruses Yen-wen Kuo's Google Scholar page Vineyard Team Programs: Juan Nevarez Memorial Scholarship - Donate SIP Certified – Show your care for the people and planet   Sustainable Ag Expo – The premiere winegrowing event of the year Sustainable Winegrowing Education On-Demand (Western SARE) – Sign Up! Vineyard Team – Become a Member Get More Subscribe wherever you listen so you never miss an episode on the latest science and research with the Sustainable Winegrowing Podcast. Since 1994, Vineyard Team has been your resource for workshops and field demonstrations, research, and events dedicated to the stewardship of our natural resources. Learn more at www.vineyardteam.org.   Transcript Craig Macmillan  0:00  Our guest today is Yen-Wen Kuo. And she is Assistant Professor in the Department of Plant Pathology at UC Davis. I'm Craig Macmillan, your host, and I'm very excited to have Dr. Koh here with us today. Welcome.   Yen-Wen Kuo  0:11  Thank you for having me.   Craig Macmillan  0:13  So you've been doing some interesting work the lab on interference RNA, and also how it affects plant viruses and possibly insects in the future. Can you explain for those of us that did not take genetics like we were supposed to in college, what interference RNA is and how it works?   Yen-Wen Kuo  0:29  Sure. So RNA interference is a biological process in which certain types of RNA RNAs can trigger RNA interference. And then once it's triggered, it will produce specifics more RNAs, that can regulate gene expression, by degrading or binding to the target RNAs containing a homologous sequence containing a similar sequence of those small RNAs. So this is a general concept of RNA interference, we also call it RNAi is very complicated the whole process. And there are different pathways and mechanisms included in the RNA interference. RNAi is a primary and effective antiviral defense in plants, but also found in some fungi and insects and lower eukaryotes. And because of all these different mechanisms, scientists and researchers, they they work on different aspects of this mechanism for either plants or animals. And they're also looking for different potential and better ways to use RNAi for different applications.   Craig Macmillan  1:45  So if I understand correctly, you have cell and there is DNA in that cell, and there's genes that code for certain things. And so the RNA is was transmitting or was carrying information from that's encoded with the gene out into the world to do something, is that a fair explanation?   Yen-Wen Kuo  2:05  So the genome there in plants or animals and human is their DNA genomes is DNA, and then the DNA will transcribed into RNA. And those RNA, some of the messenger RNAs can translate into proteins. So it's a how the central dogma from DNA makes RNA and then RNA makes protein. In the old days, we thought that oh, the protein is the important things because the protein can have different functional, different functions in different ways to to regulate everything in the body or in different organisms. But then afterwards, we found that actually RNAs they have many different forms and they can function at the RNA level. So it can interfere with gene expressions and many different things.   Craig Macmillan  3:03  And how does this apply to plant viruses because you've done some really exciting work with Gemini viruses, I believe with grapevine virus a Tell me a little bit about that work and how that works.   Yen-Wen Kuo  3:15  A lot of plant viruses, they are RNA viruses, a lot of those devastating viruses in grapevines, for example, grapevine leaf roll associated virus or grapevine red blotch virus they. So grapevine leaf roll associated viruses and RNA virus and grapevine red blotch is DNA virus. So there are different types of viruses. And so my work is trying to use different viruses making them into viral vectors to induce RNAi in Grapevine plants, to target those important viruses causing diseases in the field for the grapevines. And because so for example, when the viruses they are infecting plants, they will trigger RNAi in the plant, so that plants can protect themselves from virus infection. And because of that, we're trying to develop viral vectors can trigger RNA interference to target those viruses that's causing diseases. The work I have on the grapevine Gemini virus A that GGVA is to either develop the virus into viral vectors to target RNA virus first. So that's the initial plan for us to use. GGVA the grapevine Gemini virus A target grapevine leaf roll associated viruses. So before we eventually target that virus, we have to do a lot of different tests. We need to know if the clones the constructs or DNA constructs we have of this, GGVA can actually affect Gravelines plants, so we have to do that. And then we want to see if we can develop it into viral vector to carry the sequence we want them to express in grapevines to do the work we want them to do. So then we use it to target genes in the plants to see if they can silence the genes in the plants. So then we did that, we found that yes, we can use that viral vector to silence genes in plants. And then now we try to see that if we can use this viral vector to target other RNA viruses, or other grapevine RNA viruses, because we are actually at the same time developing different viral vectors, and one of them is GBA, is grapevine virus, a another's name, it can be very confusing. GGVA is a DNA virus. GVA is an RNA virus totally different to viruses. So since we have both viruses in the lab, so first, we try to prove the concept. We use the GGVA, the DNA virus, to target the GBA wild type virus, to see if we can see any effects. The GBA infection viral titers in the infected grapevines. So this is what we're working on right now. And so eventually, we want to use this viral vector, and potentially other viral vectors to to target grapevine leaf roll associated virus. And maybe we can use it to target mealybugs too.   Craig Macmillan  6:35  How are these vectors introduced to the plant?   Yen-Wen Kuo  6:38  We modify from the previous reports how people try to deliver those constructs the plasmids into grapevines. Most of the experiments or the assays, from before, they needed to have grapevine plants grown from in vitro, on media or from embryos. But that's really a lot of work. And it will be harder to have applications in the field. So then we develop vacuuming filtration method that we can directly vacuum infiltrate those plasmids that those DNA construct plasmids directly into the greenhouse grown grapevine plants. So those plants are propagated from the cuttings and then those plants, they are usually maybe 12 to 19 inches high above the soil when we infiltrated those plasmids into those grow vine plants. So this is an we got pretty good results, we successfully introduced those DNA constructs into the grapevine plans and those constructs can be infectious and initiate the whole the virus replicate in the grapevine.   Craig Macmillan  7:50  So is this something that can be done in a nursery then with new plants? And basically, they then would come with the vector or is it something you could do in the field?   Yen-Wen Kuo  7:57  Yes, I think the plan is that we can introduce those plasmas in the nursery in greenhouse plants before we plant them into the field. So then the plants that's planted into the field, they can have this viral vector to protect the plants from specific viruses.   Craig Macmillan  8:18  Got it. That's really neat. That's a great idea. And it's pretty cool. So that's fantastic. And in the work that you're doing so far, it sounds really exciting. And it sounds like the direction that you're kind of going in the future is with leaf roll virus that you mentioned. And then also, interaction with mealybugs you mentioned. Can you tell me more about that? What's that work all about?   Yen-Wen Kuo  8:39  Because this virus does GGVA and other viral vectors we're working on to a lot of viruses infecting grape vines, their phloem limited virus, so this GGVA is also phloem limited, meaning that the virus is can only infect the tissues around or in the phloem  is restricted. It doesn't go to like mesophyll cells or epidermal cells in infected plants, because mealybugs they feed on phloems. So we think if they can pick up those RNA interference signals, may be those RNA interference signals those small RNAs can target mealybugs too. So we can choose different target sequences in mealybugs. Hopefully you can see some effects for many bucks to to prevent that from transmitting viruses or have lethal effects for mealybugs. That's the plan. Hopefully we can do that. But we have to do tests to see how the efficacy and everything though it can have mealybugs, because there are previously they are different studies they use RNAi on insects, and many people prove that they can see some effects. We hope that the viral vector approach can also use for really apply this into the field for grapevine plants.   Craig Macmillan  10:00  What kind of index on insects are we talking about?   Yen-Wen Kuo  10:03  Depends on what target genes or sequences we choose. For my first choice, I would like to have a target that can prevent the transmission of the virus by mealybug, that will be my choice. I'm not sure if it's good to kill the insects, if it's going to affect the ecology too much. So if we can make the mealybug not transmitting the virus or other diseases, I think there will be a very good first step if we can see a lower transmission rate. And and then we can see if we need to adjust from there.   Craig Macmillan  10:40  That is amazing. And we haven't, yeah, the little bit of research that I did we have we do have proof of concept basically on this in other cropping systems. Is that right?   Yen-Wen Kuo  10:55  Yes,   Craig Macmillan  10:55  Can you tell me a little bit more about that, because that might give us some some vision of where we might go in the vineyard industry.   Yen-Wen Kuo  11:01  So, the RNAi applications, people are already trying to do some of those works. So, one example is that before people can spray double stranded RNA into the field. So, let me talk a little bit about the introduction of why using double stranded RNA. So, there are different types of RNAs that can induce RNA interference, certain types, one of them is double stranded RNA, either double stranded RNA or the single stranded RNA, they can form into a secondary structure in folding into a structure like a hairpin RNA, those are found to be able to induce RNA interference. And there's also other things like artificial micro RNAs, there are different types of RNAs that can induce RNAi and most convenient ways to make double stranded RNA. And people have been synthesizing the double stranded RNA or using bacteria to produce those double stranded RNA and then spraying to the field to get some protection for the plants. It worked at some level, but it's just not stable enough. Although double stranded RNA is more stable compared to single stranded RNA, steroids and RNA can be degraded in the field with the sun and everything the whole environment it can be degraded, people started to look for ways like bio clay to protect the RNA, and then so, they can spray in the field. So, the RNA can last longer and cause the effects. So, those double stranded RNAs can be absorbed by the insects, they can pick up from the surface of the plant or the plant can absorb those double stranded RNA into the plants. So, those are different ways and people started to see some effects on that, but still, we have to improve those different methods delivering double stranded RNA or other types of RNA to induce RNA interference in the plant. So, they are different different approaches. So, one of that is now we are trying using virus to introduce the RNAi to induce the RNAi in the plants. So, people are trying different ways to deliver those specific RNAs to induce RNAi to target specific diseases, sometimes not just viral diseases, that they will try to target fungal disease or something else and insects. This is what many different groups they are trying to do also previously, another way is to try to make transgenic plants. So if we can make plants to express those RNAs that can induce RNAi targeting to specific diseases, then you don't need to really use any tool to the deliver because the transgenic plants itself can produce those RNAs doing to induce RNAi plants. So that's also another way that people are trying to do we call that host induced gene silencing HIGS, and the virus induced gene silencing is the way my group is working on and we call it VIGs vigs. So there are different ways that which we would use to introduce those RNAs to induce RNAi in the plants.   Craig Macmillan  14:31  And right now you are at the greenhouse stage, if I understand correctly.   Yen-Wen Kuo  14:35  Yes.   Craig Macmillan  14:36  Have you introduced mealybug into your experiments into your work yet?   Yen-Wen Kuo  14:40  Not yet. We are just working on targeting grapevine virus first to see the effects. So where we have to continue monitoring those tested plants to see if the effects can last long, and the efficacy and how good they can be. So now we're at four for five months, so it's still we can see the targeted virus is being suppressed in a very, very low titer. So GVA can cause some symptoms in the grapevine plants when they see the plans are infected. But we have to peel off the bark to see the symptoms, we want to see that after targeting to the GBA virus, we saw that the viral titer is very low, if we can see that, also, the symptoms is not there anymore, is now like wild type, when when the virus was infecting in the plants alone, if we can see the difference, we don't even see the symptoms there will be really great. And this part, hopefully I can collaborate with the collaborators, Maher, he's run the foundation plan services, he can help my group on this, to see that how good the effects can be using this GGVA viral vector. So after that, if we can successfully target two different viruses, then we will start to work to change the target sequence in this viral vector to target mealybugs. So that's after the virus work.   Craig Macmillan  16:12  Yeah, well, that's very exciting. This is a really fascinating idea, and obviously is still relatively new. And I think it's really great that you and everybody else is working on this sounds like there's tremendous potential, and I hope that you folks continue on are able to continue on, is there one thing really related to this topic, you would tell growers one thing that you would advise them or you would educate them with?   Yen-Wen Kuo  16:34  I understand that there could be some concerns and maybe doubts, questioning RNAi applications in the field, because before, they already probably heard about the spray of double stranded RNA or other methods, and they saw some effects but not stable enough. So they may have some concerns or doubts, I think many scientists are trying different delivery methods that can be applied efficiently in the field. And we will do different types of tests and trials to make sure we work on any potential issues of this technology before applying them in the field and try not to affect the whole ecology or anything in the field too. And obviously, the current approaches we have are not enough to keep certain grapevine diseases, at low enough incidence. So we have to explore more potential control approaches before those diseases get worse, and adjust the ways to manage those different grapevine diseases with this changing environment. And I think hopefully, we can all work together to achieve this same goal. And I understand this is something new, I hope everyone can keep an open mind and willing to work with us to do different trials and see if we can improve different approaches to control different diseases.   Craig Macmillan  17:58  Well, I hope so too. grape growers are very creative. And they're always looking for solutions to their problems that very much fit what you're describing. And it sounds to me, this could be another tool in the IPM toolbox that may not be the single solution may not be a silver bullet. But it sounds very exciting that it may play a very important role to improve the efficacy of other techniques we have, which is great. Where can people find out more about you?   Yen-Wen Kuo  18:22  So because I will, setting up my lab, so hopefully I can have a lab website soon. I don't have accounts at Twitter or Instagram.   Craig Macmillan  18:34  Neither do I.   Yen-Wen Kuo  18:36  I don't use social media a lot. So my email that people can reach me through the email. And hopefully, when this is up or in your podcast, I will have my lab website set up so people can find us our work, my lab website.   Craig Macmillan  18:53  And we will have links and everything else that we can find posted on the episode page at the Vineyard Team podcast website. I want to thank you for being on the program. This was really, really interesting and is a kind of a view into the future of what's possible. Yeah. Our guest today was Dr. Yen-Wen Kuo. She is with the Department of Plant Pathology at the University of California Davis. And I want to thank you for being on the podcast.   Yen-Wen Kuo  19:20  Thank you for having me on the show. I really appreciate this opportunity to talk about research to explain some details about our work to the course and hopefully, I answer some questions that growers might have. I look forward to in the future maybe collaborating with different people to make this thing to work.   Nearly Perfect Transcription by https://otter.ai

A new research perspective was published in Oncotarget's Volume 14 on July 1, 2023, entitled, “Deciphering the mechanisms of action of progesterone in breast cancer.” A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. In this new perspective, researchers Gaurav Chakravorty, Suhail Ahmad, Mukul S. Godbole, Sudeep Gupta, Rajendra A. Badwe, and Amit Dutt from Tata Memorial Centre, Homi Bhabha National Institute and MIT World Peace University summarized evidence from their studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. “This research perspective is aimed to highlight the multipronged roles of progesterone in breast cancer that underlie the associated clinical response. We also present our opinion on the role of progesterone in overcoming endocrine resistance in the patients, especially by countering the genomic effects of overexpression and mutation of ESR1 and its targets.” Non-coding RNAs, particularly DSCAM-AS1, play a regulatory role in this process, along with the upregulation of the kinase gene SGK1 and activation of the SGK1/AP-1/NDRG1 axis. Progesterone-induced modification of the progesterone receptor and estrogen receptor genomic binding pattern is also involved in orchestrating estrogen signaling in breast cancer, preventing cell migration and invasion, and improving patient outcomes. The team continues on to highlight the role of progesterone in endocrine therapy resistance, which could lead to novel treatment options for patients with hormone receptor-positive breast cancer and for those who develop resistance to traditional endocrine therapies. “Overall, while preoperative hydroxyprogesterone administration appears to be a promising strategy for improving the prognosis of patients with node-positive breast cancer, the investigation of the mechanism of actions of progesterone in breast cancer remains an important area of research that holds great promise for improving patient outcomes.” DOI - https://doi.org/10.18632/oncotarget.28455 Correspondence to - Amit Dutt - adutt@actrec.gov.in Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28455 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - breast cancer, progesterone, DSCAM-AS1, endocrine therapy About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Dr. Blake Meyers is a Member Principal Investigator at the Donald Danforth Plant Science Center and a Professor in the Division of Plant Sciences at the University of Missouri. The focus of Blake's research is on small RNAs in plants. His lab studies how RNAs are used to regulate the complex machinery of cells, particularly in the context of plant reproductive biology. When he's not conducting research in the lab, Blake loves to travel both for work and for fun. Blake strives to balance his family life with his science, and he also enjoys reading cookbooks and experimenting in the kitchen at home. He received a B.A. in Biology from the University of Chicago, and went on to receive his MS and PhD in Genetics from the University of California, Davis. Afterwards, Blake completed postdoctoral fellowships at Dupont Genomics and at the University of California, Davis. Before accepting his current positions, Blake was the Edward F. and Elizabeth Goodman Rosenberg Professor and Chair of the Department Plant and Soil Sciences of the University of Delaware. Blake is here with us today to tell us all about his journey through life and science.

There have been a lot of stories in the news over the last few months about AI chatbots like ChatGPT that can respond to your questions with convincing and well-written answers. These so-called large language models can tell you how to build a treehouse, how to bake a cake, or how to sleep better. But notice that word large. Behind the scenes, these models have learned which word tend to cluster together by sifting through hundreds of billions of pieces of data—basically the entire Internet, in the cast of ChatGPT, including all of Wikipedia and thousands of published books. Now imagine that another chatbot came along that could learn how to generate convincing text response by studying only, say, 18 sentences. Something like that is what this week's guest Raphael Townshend, the founder and CEO of Atomic AI, has accomplished when it comes to predicting the structure of RNA molecules.RNA has been in the news a lot lately too. That's in part because some of the vaccines that helped us beat back the coronavirus pandemic were made from messenger RNA, a form of the molecule that instructs cells how to build proteins (in that case, antibodies to the virus). But RNA has many other functions in the body, and if we knew how to design small-molecule drugs to attach to binding pockets on any given RNA to interrupt or modulate its functions, it could open up a whole new realm of medical treatments. The problem is, if all you know about an RNA molecule is its nucleotide sequence, it's very hard to predict where those binding pockets might be and what kind of drug might fit into them. As a PhD student at Stanford, Townshend designed a deep learning model to tackle that problem. The model, called ARES, started with a proposed structure for an RNA molecule with a known nucleotide sequence, and predict how that proposal would compare to real-world data. ARES turned out to be stunningly accurate, and it acquired its skills by studying a remarkably small training set: just 18 examples of RNAs with known structures. So in a way, it was using the power of small data, together with a bit of physics. Now Atomic AI is building on that original model to create an engine for discovering new small-molecule drugs that could potentially interrupt any disease where RNA is a player.For a full transcript of this episode, please visit our episode page at http://www.glorikian.com/podcast Please rate and review The Harry Glorikian Show on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to The Harry Glorikian Show podcast. You can find it by searching for it or selecting it from your library. Just note that you'll have to go to the series page which shows all the episodes, not just the page for a single episode.3. Scroll down to find the subhead titled "Ratings & Reviews."4. Under one of the highlighted reviews, select "Write a Review."5. Next, select a star rating at the top — you have the option of choosing between one and five stars. 6. Using the text box at the top, write a title for your review. Then, in the lower text box, write your review. Your review can be up to 300 words long.7. Once you've finished, select "Send" or "Save" in the top-right corner. 8. If you've never left a podcast review before, enter a nickname. Your nickname will be displayed next to any reviews you leave from here on out. 9. After selecting a nickname, tap OK. Your review may not be immediately visible.That's it! Thanks so much.

Videos : The Covid Redemption with Tim Robbins – #048 – Stay Free with Russell Brand MP calls for complete suspension of mRNA jab in extraordinary British Parliamentary speech Turmeric studied for its ability to seek out and destroy cancer stem cells, the source of all tumors Montclair State University, December 13, 202 Turmeric has gained immense popularity over the years not just for the unique flavor it adds to dishes like curries, but also for its various health benefits. One of its most promising therapeutic applications is as a natural remedy for cancer. Although the anticancer potential of turmeric isn't new, a recent study published in Cancer Letters further proved the importance of this golden spice in understanding and treating cancer. The team of American researchers evaluated the ability of curcumin, which is a polyphenol in turmeric, to target cancer stem cells that are assumed to be the primary cause of cancer tumor formation and malignancy. Unlike conventional cancer models used in previous studies, the cancer stem cell model suggests that only a small population of cancer cells drive the initiation, maintenance, and growth of tumors. These stem cells regularly undergo renewal and differentiation into other cancer cells, which no longer have the ability to regenerate themselves. Therefore, in this model, cancer stem cells that are not killed by treatments lead to the formation of more invasive and treatment-resistant tumors. In this study, the researchers found that curcumin is more effective in eradicating cancer since unlike conventional treatments, this polyphenol also targets cancer stem cells. It can do so through various mechanisms of action, which include the following. Regulation of cancer stem cell self-renewal pathway — There are different pathways involved in the self-renewal of cancer stem cells. These include the Wnt/beta-catenin, sonic hedgehog 89 (SHH), and Notch pathways. The researchers found that curcumin can directly or indirectly interfere with these pathways in 12 different cancer cell lines Modulation of microRNA — The body contains microRNAs, which are short RNA sequences that don't encode for anything. These microRNAs regulate more than 33 percent of protein-coding genes by targeting and binding to their corresponding messenger RNAs so that these won't be expressed. In this study, the authors observed that curcumin altered microRNA expression in cancer stem cells so that they can't produce everything that they need for tumor formation and growth. Direct anti-cancer activity — Curcumin selectively targets cancer cells and programs their death. When used in conjunction with conventional anticancer agents, this effect becomes more evident and the damage typically caused by chemotherapy is no longer observed. Overall, the results of this study show that for cancer treatments to be effective, they have to target and kill cancer stem cells just like turmeric does. Otherwise, these cancer stem cells will pave the way for the formation of more invasive and treatment-resistant tumors. (NEXT) Chiropractic spinal manipulation associated with reduction in low back surgery University Hospitals Cleveland Medical Center, December 19, 2022 A recent study from University Hospitals (UH) Connor Whole Health has found that adults who initially visit a chiropractor to receive spinal manipulation for low back pain caused by disc herniation or radiculopathy (i.e., sciatica) are less likely to undergo discectomy (i.e., disc surgery) over the subsequent two years. This study was recently published in the journal BMJ Open. In this retrospective cohort study, the authors selected adult patients, age 18 to 49, from a 101 million patient United States health records network (TriNetX, Cambridge, MA, U.S.). Patients with serious pathology or urgent indications for surgery were excluded from the study. Ultimately, the authors identified 5,785 patients who initially received chiropractic spinal manipulative therapy, and the same number of patients who received other forms of medical care for their low back pain. The authors used a statistical technique called propensity score matching to control for variables that could influence the likelihood that patients would undergo discectomy. In this process, they matched patients in both cohorts according to several such as age, sex, obesity, smoking, previous injections, and medications. The authors found that patients who initially received chiropractic spinal manipulation for their low back pain were significantly less likely to undergo lumbar discectomy through two years' follow-up. At one year follow-up, 1.5% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.2% of patients in the cohort receiving other care At two years' follow-up, 1.9% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.4% of patients in the cohort receiving other care This study represents the first study to examine whether chiropractic care is associated with a reduction in likelihood of discectomy. (NEXT) High-intensity exercise delays Parkinson's progression Northwestern Medicine and University of Denver, December 11, 2022 High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine and University of Denver scientists. This is the first time scientists have tested the effects of high-intensity exercise on patients with Parkinson's disease, the second most common neurodegenerative disorder and the most common movement disorder, affecting more than a million people in the United States. It previously had been thought high-intensity exercise was too physically stressful for individuals with Parkinson's disease. “If you have Parkinson's disease and you want to delay the progression of your symptoms, you should exercise three times a week with your heart rate between 80 to 85 percent maximum. Because medications for Parkinson's have adverse side effects and reduced effectiveness over time, new treatments are needed. The randomized clinical trial included 128 participants ages 40 to 80 years old from Northwestern University, Rush University Medical Center, the University of Colorado and the University of Pittsburgh. Participants enrolled in the Study in Parkinson Disease of Exercise (SPARX) were at an early stage of the disease and not taking Parkinson's medication, ensuring the results of the study were related to the exercise and not affected by medication. “The earlier in the disease you intervene, the more likely it is you can prevent the progression of the disease,” Corcos said. “We delayed worsening of symptoms for six months; whether we can prevent progression any longer than six months will require further study.” Scientists examined the safety and effects of exercise three times weekly for six months at high intensity, 80 to 85 percent of maximum heart rate, and moderate intensity, 60 to 65 percent of maximum heart rate. They compared the results to a control group who did not exercise. After six months, participants were rated by clinicians on a Parkinson's disease scale ranging from 0 to 108. The higher the number, the more severe the symptoms. Participants in the study had a score of about 20 before exercise. Those in the high intensity group stayed at 20. The group with moderate exercise got worse by 1.5 points. The group that did not exercise worsened by three points. Three points out of a score of 20 points is a 15 percent change in the primary signs of the disease and considered clinically important to patients. It makes a difference in their quality of life. (NEXT) Meditation adapts the brain to respond better to feedback University of Surrey UK, December 11, 2022 In a study in the Journal of Cognitive, Affective & Behavioral Neuroscience researchers from the University of Surrey have discovered a link between meditation and how individuals respond to feedback. Participants in the study, a mixture of experienced, novice and non-meditators, were trained to select images associated with a reward. Each pair of images had varying probabilities of a reward e.g. images that result in a reward 80 per cent of the time versus those that result in a reward 20 per cent of the time. Participants eventually learnt to select the pairing with the higher outcome. Researchers found that participants who meditated were more successful in selecting high-probability pairings indicating a tendency to learn from positive outcomes, compared to non – meditators who learned the pattern via low-probability pairings suggesting a tendency to learn from negative outcomes. During the study participants were connected to an EEG, a non-invasive method that records electrical patterns in the brain. Results from the EEG found that while all three groups responded similarly to positive feedback, the neurological response to negative feedback was highest in the non-meditation group, followed by the novice group and then by the experienced meditation group. These results indicate that the brains of meditators are less affected by negative feedback, and that this may be a result of altered dopamine levels caused by meditation. Paul Knytl, lead author and PhD candidate in psychology at the University of Surrey, said: “Humans have been meditating for over 2000 years, but the neural mechanisms of this practice are still relatively unknown. These findings demonstrate that, on a deep level, meditators respond to feedback in a more even-handed way than non-meditators, which may help to explain some of the psychological benefits they experience from the practice.” (NEXT) Caution to pregnant women on red meat diabetes link University of Adelaide (Australia) December 12, 2022 Pregnant women and women planning to become pregnant can make use of the holiday season to adjust their diets and reduce the risk of gestational diabetes, according to researchers at the University of Adelaide's Robinson Institute. The recommendation comes at a time when there is increasing evidence to suggest that red meat is linked with a higher rate of gestational diabetes in pregnant women, which poses risks to the health of both the mother and the baby. In a commentary published in the jjournal Evidence-Based Nursing, author Philippa Middleton says the latest international research shows that women who eat a lot of red and processed meats even before they become pregnant have a significant risk of developing gestational diabetes. “There have been several reports linking red meat with increased risk of type 2 diabetes, and now the work of a number of research teams worldwide is showing this link for diabetes during pregnancy,” says Ms Middleton, who is one of the Robinson Institute's research leaders. “While this news is alarming, there are also some positives. The latest research from the United States has shown that eating fish and poultry does not increase the risk of gestational diabetes, and consuming more vegetable and non-meat protein is associated with a reduction in risk. “For example, just over half a serving of nuts per day can reduce the risk of gestational diabetes by 40%.” “Based on current evidence, pregnant women or women planning to become pregnant should consider eating more vegetable protein, and nuts, and replacing some red meat with fish and poultry. (NEXT) Treatment for lupus may depend on restoring proteins in patients' blood Singapore General Hospital, December 19, 2022 Restoring protein balance in the blood may be key to developing an effective treatment for lupus. The incurable autoimmune disease reportedly affects about 100 in every 100,000 people worldwide, and disproportionally affects women between 15 and 45 years-old and Asians. Lupus causes the body's immune system to attack itself, which can inflame several vital organs like the kidneys, brain, heart, and lungs. The aggressive nature of the disease is what makes it life-threatening for many who have it, especially since current treatments don't help that much. “We are excited about the possibility of a new treatment option for lupus as 30 to 60 percent of patients do not respond to conventional medications despite aggressive regimens. In the past 65 years, only three drugs for lupus have been approved by the United States Food and Drug Administration but these drugs have modest efficacy. There is therefore a real and urgent need for better therapies, particularly for the more severe spectrum of lupus that we see in Asia,” says senior author Andrea Low, the Head and Senior Consultant in the Department of Rheumatology & Immunology at Singapore General Hospital (SGH), in a media release. To reach their findings, Low and her team studied CXCL5, a protein that helps to regulate the immune system through neutrophils, which are a type of white blood cell. They revealed that lupus patients had considerably lower levels of the protein in their blood compared to healthy people, thus suggesting that it may have a connection to the disease. They also discovered that mice with severe lupus injected weekly with CXCL5 displayed restored protein balance. Moreover, their survival outcomes increased from 25 percent to over 75 percent after 10 weeks. Not only did the injections reduce mortality risk, but they didn't cause any adverse side-effects, study authors report. “Our study has shown CXCL5 to be safe. There was no liver or kidney toxicity or cancer inducing effects. Major components of the immune system were also not compromised,” reports principal investigator Dr Fan Xiubo, Senior Research Fellow, Department of Clinical Translational Research, SGH. The entire team is hopeful that they can continue to build on their research to better the lives of patient's suffering from this debilitating disease. “To be in the forefront of medicine means we have to constantly further our understanding of diseases and offer patients better treatment options through rigorous scientific research. I'm heartened that the team has shed new light on lupus and the possibility of a more efficacious therapy for patients some years down the road,” says Professor Fong Kok Yong, Deputy Group CEO (Medical and Clinical Services), SingHealth, and Senior Consultant, Department Rheumatology & Immunology, SGH