Podcast appearances and mentions of watson crick

Celebrating wins is not about ego—it is about visibility and honoring the work you are doing, even when it feels uncomfortable to say out loud. Lesley Logan shares the powerful and often-overlooked story of Rosalind Franklin, using it as a reminder of what can happen when contributions go unclaimed. From a meaningful community win to a personal birthday mindset shift, this FYF episode encourages you to stop playing small and let yourself be known for the work you're doing. Because when people can see your work, they can actually be helped by it. If you have any questions about this episode or want to get some of the resources we mentioned, head over to LesleyLogan.co/podcast https://lesleylogan.co/podcast/. If you have any comments or questions about the Be It pod shoot us a message at beit@lesleylogan.co mailto:beit@lesleylogan.co. And as always, if you're enjoying the show please share it with someone who you think would enjoy it as well. It is your continued support that will help us continue to help others. Thank you so much! Never miss another show by subscribing at LesleyLogan.co/subscribe https://lesleylogan.co/podcast/#follow-subscribe-free.In this episode you will learn about:Rosalind Franklin's uncredited role in discovering DNA.How her research was used and published without permission.A community win from Ainsley sparked by taking action together.Lesley's reflection on why talking about your work matters.How a new birthday theme restored excitement around celebrating.Episode References/Links:Submit your wins or questions - https://beitpod.com/questionsHer Wiki - https://www.instagram.com/p/DQOCW0ajNNYThe Art of Gathering by Priya Parker - https://a.co/d/8WYiDU0 If you enjoyed this episode, make sure and give us a five star rating and leave us a review on iTunes, Podcast Addict, Podchaser or Castbox. https://lovethepodcast.com/BITYSIDEALS! DEALS! DEALS! DEALS! https://onlinepilatesclasses.com/memberships/perks/#equipmentCheck out all our Preferred Vendors & Special Deals from Clair Sparrow, Sensate, Lyfefuel BeeKeeper's Naturals, Sauna Space, HigherDose, AG1 and ToeSox https://onlinepilatesclasses.com/memberships/perks/#equipmentBe in the know with all the workshops at OPC https://workshops.onlinepilatesclasses.com/lp-workshop-waitlistBe It Till You See It Podcast Survey https://pod.lesleylogan.co/be-it-podcasts-surveyBe a part of Lesley's Pilates Mentorship https://lesleylogan.co/elevate/FREE Ditching Busy Webinar https://ditchingbusy.com/Resources:Watch the Be It Till You See It podcast on YouTube! https://www.youtube.com/channel/UCq08HES7xLMvVa3Fy5DR8-gLesley Logan website https://lesleylogan.co/Be It Till You See It Podcast https://lesleylogan.co/podcast/Online Pilates Classes by Lesley Logan https://onlinepilatesclasses.com/Online Pilates Classes by Lesley Logan on YouTube https://www.youtube.com/channel/UCjogqXLnfyhS5VlU4rdzlnQProfitable Pilates https://profitablepilates.com/about/Follow Us on Social Media:Instagram https://www.instagram.com/lesley.logan/The Be It Till You See It Podcast YouTube channel https://www.youtube.com/channel/UCq08HES7xLMvVa3Fy5DR8-gFacebook https://www.facebook.com/llogan.pilatesLinkedIn https://www.linkedin.com/in/lesley-logan/The OPC YouTube Channel https://www.youtube.com/@OnlinePilatesClasses Episode Transcript:Lesley Logan 0:00  It's Fuck Yeah Friday, Brad Crowell 0:01  Fuck yeah. Lesley Logan 0:02  Get ready for some wins. Welcome to the Be It Till You See It podcast where we talk about taking messy action, knowing that perfect is boring. I'm Lesley Logan, Pilates instructor and fitness business coach. I've trained thousands of people around the world and the number one thing I see stopping people from achieving anything is self-doubt. My friends, action brings clarity and it's the antidote to fear. Each week, my guest will bring bold, executable, intrinsic and targeted steps that you can use to put yourself first and Be It Till You See It. It's a practice, not a perfect. Let's get started. Lesley Logan 0:44  Hi, Be It babe. Happy birthday weekend. Well, it's my birthday weekend. Is it your birthday weekend? I know a lot of Aquarians. Hi. It's actually a Fuck Yeah Friday episode, and that means we celebrate wins that you've sent in, a win of mine. We start to see how wins can exist everywhere, and a little mantra for our weekend. So, first, have to do the inspiration. First have to do inspiration. I am so sorry. It's my own show, and I forgot my own order, also laughing to myself, because I actually went in to do this, and then got distracted with my ADHD, and then then I got distracted, and now I'm here. So welcome. Welcome to a podcast with someone with ADHD. You know, we're just we're just making it work. Lesley Logan 1:26  Okay, so here we go. Here's the inspiration that I found, and I this is really cool. Oh, this is really cool. So excited. This blew my mind, and I'm so excited to share with you. 70 years ago, a woman discovered the structure of DNA, but two Cambridge men stole her work and won the Nobel Prize. She was erased from history and died of cancer. This is a story of the biggest theft in science, and its main character, Rosalind Franklin. So at the King's College in London, a brilliant young scientist made groundbreaking discoveries about DNA structure. Her name was Rosalind Franklin, using advanced X ray crystallography, she captured the clearest images of DNA ever seen inside the famous photo 51 and here's why it was important. And you can get this on her Wiki org. Photo 51 was revolutionary. So there's an image of this like, you know, it looks kind of like a baseball. After 100 hours of X ray exposure had showed clear X patterns that suggest a helical structure. Franklin has already concluded that DNA likely had a regular, repeating structure, but was meticulously gathering more and more data before publishing. On January 30th 1953 the theft that changed biology occurred in a dimly lit King's College London office. Maurice Wilkins took out a folder containing Photo 51, Franklin's clearest X ray image of DNA, and showed it to James Watson. When Watson saw the photo, he reportedly became so excited he could barely concentrate. The X pattern was precisely what he and Crick needed. He rushed back to Cambridge, sketching the image from memory on a newspaper during his train ride. Within hours of returning, Watson and Crick began building their now famous metal model of DNA. They use Franklin's precise measurements from Photo 51 data, they had no permission to access, determine the exact dimensions of their model. Their paper announcing DNA structure was published on April 25th 1953. Franklin's own paper appeared on the same issue. However, it was placed third after Watson and Crick's despite containing the critical experimental evidence that proved their model, Franklin's only credit, a brief acknowledgement of having been stimulated by general knowledge of her work. The reality, without her Photo 51 and unpublished analysis, Watson and Crick would have been discovered months or years behind. Discovery would have been months or years behind. The final result came. Final insult, excuse me, came in 1962 Watson Crick and Wilkins shared the Nobel Prize in Medicine. Rosalind Franklin never saw that recognition. She died of ovarian cancer in 1958 at just 37 years old, likely caused by her extensive work with X ray radiation, Franklin's story is evidence of disturbing pattern science. Women's contributions get being minimized, credit taken by male colleagues, critical discoveries going unrecognized. Even Watson's 1968 book the double helix portrayed her dismissively, the truth emerged slowly over decades, her X ray work was crucial. Without Photo 51 no DNA model. Her mathematical analysis was pioneering. Her experimental techniques were groundbreaking. Today, Franklin is finally being recognized multiple buildings and programs named after her. Her face on medical walls, books document her achievements a Mars rover named Rosalind, but she never knew her true impact. Rosalind Franklin died, never knowing she'd helped unlock one of science greatest mysteries, but our rigorous methods, brilliant mind and dedication to truth exemplify what genius really means. I just think, you know, I mean, like, it's, how is it like? Is that positive? Like, now we recognize her and we didn't before, and I just think that, like, sometimes it's really, I think the moral is like, yay. Well, not the moral, but first of all, yay that we celebrate her, and yay now that we know this. And also you're gonna do some crazy amazing things, and someone else is gonna get a win, and it can suck so much, and it hurts, and so first of all, brag about what you're fucking doing. Do it. Brag about it, and I know that word is, like, really hard for a lot of us, women over a certain age, because we were told, like, never to brag, to be quiet, like it's actually ugly and it's not attractive, to brag and you have an ego. Bullshit. No. People need to know the work that you're doing and the work that you're working on so that you you can be the person known for it, right, for the things that you're doing, and I definitely struggle with that a lot. And luckily, like having to put myself out there has really helped me realize that, like, the impact that I'm making is is incredible, and the people who are impacted are doing amazing things that are impacting others, and it's a domino effect. So who am I to play small not talk about the things I'm doing, because then people who need the help that I have don't get it. People who need the help that you have don't get it, they don't know. So brag about yourself a little bit. And I, I love what Rosalind Franklin did, and I just there are, I encourage you, like if you're needing a bit of inspiration, and just like someone to help you, like, get yourself up and keep going, is find books that celebrate the women in history, because there's so many we didn't learn about because they didn't tell us, didn't tell us. So we have to go after it. Go look at it. Lesley Logan 6:33  All right. Let's get to some wins of yours. Here we go. This one is from, oh, it's our lovely Ainsley. My win's from San Fran. These photos pretty much sum it up, having so much fun in San Francisco, going to different studios with Jennifer Maison, a road trip to Sacramento with a show around at the Balanced Body headquarters by lovely Paul, chatting about our Cambodia times, they were all at the retreat in Cambodia together, and then the sushi adventures with Christine Kam-Lynch. Lesley, thank you for bringing us all together. You have dreams of creating community, and your dreams are making our dreams come true, sending me on adventures that would honestly explode my imagination if you would tell me three years ago that this is what I'd be doing. I trusted your process, and this is wild. Thank you. It was an incredible five days. PS, Lesley, I've only just seen the video sent to you. It was birthday margaritas. I'm so freaking proud of you, Ainsley, I'm so freaking proud of you. You know what's fun is, like, even if you had told me, like, if I had been told, like, oh, like, in five, in three years, I'm gonna be doing this, like, I'd be like, okay, great, I love this. Let's figure out we're gonna do it right, like I would believe it, and I'd still be wowed when it happened, because like so few people do what they say they're gonna do, so few people put the work in. I am so obsessed with all that agency and eLevate and OPC members do, because I know they're a fraction of the people out there who will actually do what they said they're going to do. They're a fraction. And so when they do it, I am so freaking excited for them. I love guiding people. You know, you thank me so much, and I, and I do take all of that, I receive all that gratitude. Because seven, well, gosh, how long has eLevate been around, Agency been around? Agency's been around since 2018. Eight years. Like, eight years ago, I didn't know what I was creating, but I knew what I wanted to create. And sitting here reading this win, I get to go, it's like a win for me too, because I get to go, wow. Like we did it. We created this community that expands continents, and people meet up with each other, and they take action, and I'm just so I'm just so stoked for you guys. I like, can't even get the words out. I'm so freaking stoked reliving that win, and though that video was so fun, and reliving what you're doing and but also, like, you have to be proud of what you're doing, because it's actually when I bring people together that isn't easy. But like, it's easy for you, right? Like, I bring people but you guys have to take the next step. You guys had to plan the trip and take the action, and you guys had to commit to it. And then amidst all that was going on, all of your lives still show up and do it. So many people won't, because there's a should have, could have, maybe I should be doing this instead. I'm just like, Thank you for celebrating this win with us, because I know you're inspiring other people to take action and allow themselves to be surprised by what could happen in just a short period of time, just three years, right? We think that's so long and it's so short, I can't believe it's only been three years since we've been doing this. So thank you. Lesley Logan 9:32  Okay, my win. So it's my birthday on Monday, (inaudible). I'm so excited about it, and I know I've celebrated past birthdays, like, I'm like, I love that like, I don't even care that. I'm like, it's another year on the book. It's like, it's like, so fun. But I will say, like, before Covid, I had the most fun birthday parties, and I loved it. And then after covid, you know, there just wasn't a lot of ways to, like, gather people together. Like, I had my first in-person birthday in Vegas. It was my second birthday here, and it was, I was looking at pictures about, like, I don't even know who these people are, because I didn't, I didn't know people. So like, just random people showed up, and that was a win. But then the 2023 and 2024, 2025, I just, 2025, I had, I actually, actually did have a birthday party, and that was really fun. But 2022, 2023 and 2024 I just really wasn't excited to celebrate my birthday. And it's not because I wasn't excited to get older. It's not because I was like, oh, like, I just was like, I just want to be on a vacation. I'm just a little tired. And that's because, like, as the business was growing and we thought we prepared ourselves for the growth of the business, you reflect and refine and go, oh, I should have been two months ahead, not just one month ahead. I should have been like, so you learn from these things, right? But it can take a year to put those new changes to effect. We always want things to happen tomorrow. That's just not how it goes, right? Like, some things do take time. At any rate, I would get to my birthday and I'm just like, I just don't even have the time for the invitations. I just don't even have the time to plan. I just want to, like, spa life. I just want to go to Mexico, like, so I did those things, right? And I'm proud of I'm proud of everything I did. I have great celebrations. But I really did want to have, like, a fun birthday. And I wanted to go back to having fun birthdays and excitement. Last year's was actually a great time. And so I'm like, oh, I remember how great these were. So Priya Parker, I think I told this as, like, an inspirational thing. Priya Parker had posted, she's the author of The Art of Gatherings, great book. And she posted, you know, this thing of, like, dressing for the wrong party party. And so I was like, I'm obsessed with this. Because first of all, everyone who has a January birthday or a late December birthday knows like, no one is excited for your birthday. Some people are doing dry January. Some people are broke because they just got their credit card bill from their holiday. Some people are sick. Like, it's just not like, not the thing. So I definitely have been like, there needs to be a reason to come. And I don't know if this will be an annual theme, because I don't know if people get bored with it, but I freaking love it. I love it. So I threw myself a dress for the wrong party party. It's happening this weekend, so I can't tell you what everyone dressed like, or what I dress up like, because now that it's like, I can dress however I want. I might change my outfit, I don't even know, but I have made the invites. I've sent them out. I have excitedly done it, not reluctantly done it. And so my win is I just found a way to get excited about the thing that I wanted to do, and I just wanted to share that with you, because, like, maybe it's not your birthday, but maybe there's like, things in your life that you know you want to do, but like, there's not an excitement around it. And I encourage you to figure out, like, what is, what is the thing that's surrounding the thing that you want to do that's blocking you from excitement? My, my win I think I just needed a new theme to do the birthday, and it made me so excited to do it. So that's my win. I did it. I no longer. I'm like, oh, it's my birthday. I guess I'll throw something together like I am freaking having a good time. And my husband, if he's listening to this, would go, we're having a good time. There's a funny comedian who does that. And so anyways, if you know him, then you'll have to. Lesley Logan 12:58  All right, my love and affirmation for you to take with you on my birthday weekend, I am complete as I am, others simply support me. I am complete as I am, others simply support me. I am complete as I am, others simply support me. Babe, you are complete as you are, and we are here to support you. So until next time, Be It Till You See It. Lesley Logan 13:23  That's all I got for this episode of the Be It Till You See It Podcast. One thing that would help both myself and future listeners is for you to rate the show and leave a review and follow or subscribe for free wherever you listen to your podcast. Also, make sure to introduce yourself over at the Be It Pod on Instagram. I would love to know more about you. Share this episode with whoever you think needs to hear it. Help us and others Be It Till You See It. Have an awesome day. Be It Till You See It is a production of The Bloom Podcast Network. If you want to leave us a message or a question that we might read on another episode, you can text us at +1-310-905-5534 or send a DM on Instagram @BeItPod.Brad Crowell 14:06  It's written, filmed, and recorded by your host, Lesley Logan, and me, Brad Crowell.Lesley Logan 14:11  It is transcribed, produced and edited by the epic team at Disenyo.co.Brad Crowell 14:15  Our theme music is by Ali at Apex Production Music and our branding by designer and artist, Gianfranco Cioffi.Lesley Logan 14:22  Special thanks to Melissa Solomon for creating our visuals.Brad Crowell 14:26  Also to Angelina Herico for adding all of our content to our website. And finally to Meridith Root for keeping us all on point and on time.Transcribed by https://otter.aiSupport this podcast at — https://redcircle.com/be-it-till-you-see-it/donationsAdvertising Inquiries: https://redcircle.com/brandsPrivacy & Opt-Out: https://redcircle.com/privacy

TWiV explains the 1953 paper by Watson & Crick proposing a structure for DNA, and the role of Epstein-Barr virus in triggering the autoimmune disease systemic lupus erythematosus. Hosts: Vincent Racaniello, Kathy Spindler, and Brianne Barker Subscribe (free): Apple Podcasts, RSS, email Become a patron of TWiV! Links for this episode Support science education at MicrobeTV Immune 100 live at the Incubator CDC revives debunked 'link' between childhood vaccines and autism (npr) A structure for deoxyribose nucleic acid (Nature pdf) Three Papers, Three Lessons (Am J Resp Crit Care Med) Discovery of Double Helix (Crick Papers) Jim Watson was blinded by DNA (NY Times) What Rosalind Franklin contributed (Nature) EBV reprograms autoreactive B-cells in lupus (Sci Transl Med) EBV and the making of lupus (Sci Transl Med) Timestamps by Jolene Ramsey. Thanks! Weekly Picks Brianne – Virus snowflakes Kathy – When "Physic(k)s Lost Its 'k' and other Language Quarks Vincent – The Peripheral by William Gibson Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv Content in this podcast should not be construed as medical advice.

Wer kennt sie nicht: Watson & Crick, Albert Einstein, Max Planck und all die großen Namen von Genies in der Wissenschaft. Aber welchen Anteil hatte eigentlich Rosalind Franklin an der Entschlüsselung der DNA Struktur? Wer war Mileva Maric? Warum sind so viele herausragende Wissenschaftlerinnen der Geschichte unsichtbar - und ist die Situation heutzutage überhaupt besser? Wir begeben uns auf einen kleinen Streifzug durch die Geschichte der Wissenschaft und analysieren aktuelle Studien um genau dies herauszufinden.

It is the famous lightbulb-going-off story every school kid learns: How James Watson and Francis Crick discovered the structure of DNA, cementing their place in scientific history. But as William Brangham explains, a new book titled "The Secret of Life" paints a more troubling picture of how this famous discovery came about, and why scientist Rosalind Franklin also deserved credit. PBS NewsHour is supported by - https://www.pbs.org/newshour/about/funders

Découvrez le deuxième épisode de notre cycle sur Rosalind Franklin. Dans cet épisode, nous évoquerons les études à l'Université de Cambridge, sa période parisienne enchantée ainsi que ses premiers mois au sein du King's College de Londres, où elle travaillera sous la direction de Maurice Wilkins.

Compared to other foundational scientific breakthroughs like Mendeleev's periodic table, Einstein's relativity, and Watson Crick and Franklin's double helix DNA model, the discovery of plate tectonics is the youngest and one of the most influential in the Earth Sciences. Since the 1960's geoscientists have been building upon John Tuzo Wilson's groundbreaking plate tectonic theory including Dr. Oguz Gogus who is a professor of geophysics from Istanbul's Technical University. We discuss the continental drip theory, which explains why the geologically active region of Central Anatolia has been uplifted over a very short period of geologic time. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.30.362251v1?rss=1 Authors: Kamble, P., Hall, K., Chandak, M., Tang, Q., Caglayan, M. Abstract: DNA ligase I (LIG1) completes base excision repair (BER) pathway at the last nick sealing step following DNA polymerase (pol) {beta} gap filling DNA synthesis. We previously reported that pol {beta} 8-oxo-2'-deoxyribonucleoside 5'-triphosphate (8-oxodGTP) insertion confounds LIG1 leading to the formation of ligation failure products with 5'-adenylate (AMP) block. Here, we report the mutagenic ligation of pol {beta} 8-oxodGTP insertion products and an inefficient substrate-product channeling from pol {beta} Watson-Crick like dG:T mismatch insertion to DNA ligation by LIG1 mutant with perturbed fidelity (E346A/E592A) in vitro. Moreover, our results revealed that the substrate discrimination of LIG1 for the nicked repair intermediates with preinserted 3'-8-oxodG or mismatches is governed by the mutations at both E346 and E592 residues. Finally, we found that Aprataxin (APTX) and Flap Endonuclease 1 (FEN1), as compensatory DNA-end processing enzymes, can remove 5'-AMP block from the abortive ligation products with 3'-8-oxodG or all possible 12 non-canonical base pairs. These findings contribute to understand the role of LIG1 as an important determinant of faithful BER, and how a multi-protein complex (LIG1, pol {beta}, APTX and FEN1) can coordinate to hinder the formation of mutagenic repair intermediates with damaged or mismatched ends at the downstream steps of the BER pathway. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.26.355974v1?rss=1 Authors: Beyerle, E. R., Dinpajooh, M., Ji, H., von Hippel, P. H., Marcus, A. H., Guenza, M. G. Abstract: Regulatory protein access to the DNA duplex 'interior' depends on local DNA 'breathing' fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding, present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with experiments. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.19.304816v1?rss=1 Authors: Balci, H., Globyte, V., Joo, C. Abstract: Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins, particularly Cas9, have provided unprecedented control on targeting and editing specific DNA sequences. If the target sequences are prone to folding into non-canonical secondary structures, such as G-quadruplex (GQ), the conformational states and activity of CRISPR-Cas9 complex would be influenced, but the impact has not been assessed. Using single molecule FRET, we investigated structural characteristics of the complex formed by CRISPR-Cas9 and target DNA, which contains a potentially GQ forming sequence (PQS) in either the target or the non-target strand (TS or NTS). We observed different conformational states and dynamics depending on the stability of the GQ and the position of PQS. When PQS was in NTS, we observed evidence for GQ formation for both weak and stable GQs. This is consistent with R-loop formation between TS and crRNA releasing NTS from Watson-Crick pairing and facilitating secondary structure formation in it. When PQS was in TS, R-loop formation was adequate to maintain a weak GQ in the unfolded state but not a GQ with moderate or high stability. The observed structural heterogeneity within the target dsDNA and the R-loop strongly depended on whether the PQS was in TS or NTS. We propose these variations in the complex structures to have functional implications for Cas9 activity. Copy rights belong to original authors. Visit the link for more info

Wie ihr ja schon mitbekommen habt, wissen Lorenz und Jasmin vorher nicht, was für eine Geschichte die oder der andere mit in die Aufnahme nimmt. Anscheinend sind beide jedoch mittlerweile durch diese sehr harmonische Podcast-Ehe so synchronisiert, dass sie zufällig an dasselbe Thema gedacht haben: An Diversität in der Wissenschaft, also abseits der weißen Männer. Zuerst erklärt Lorenz, wie Frauen, queere Menschen und BIPoC (durch Studien belegte!) innovativere Wissenschaft betreiben, jedoch aufgrund von struktureller Frauen-, Queer-Feindlichkeit und Rassismus im Wissenschaftsbetrieb systematisch ausgegrenzt und benachteiligt werden. Auch Jasmin hat sich mit Benachteiligungen im Wissenschaftsbetrieb befasst und erzählt, wie Watson & Crick die Forschungsergebnisse von Rosalind Franklin stahlen und mit dem darauf basierenden DNA-Modell den Nobelpreis holten, ohne sie miteinzubeziehen. Außerdem erzählt sie von Anfeindungen, denen Frauen in der Wissenschaft begegneten und bis heute ausgesetzt sind.

Bruce Ames Sr Scientist at CHORI, and Prof Emeritus of Biochem and Molecular Bio, at UC Berkeley. Rhonda Patrick Ph.D. biomedical science, postdoc at CHORI in Dr. Ames lab. The effects of micronutrients on metabolism, inflammation, DNA damage, and aging.TranscriptSpeaker 1: Spectrum's next. Speaker 2: Okay. [inaudible] [inaudible]. Speaker 1: Welcome to spectrum the science and technology show [00:00:30] on k a l x Berkeley, a biweekly 30 minute program bringing you interviews featuring bay area scientists and technologists as well as a calendar of local events and news. Speaker 3: Hi there. My name is Renee Rao and I'll be hosting today's show this week on spectrum. We present part two of our two interviews with Bruce Ames and Rhonda Patrick. Dr Ames is a senior scientist at Children's Hospital, Oakland Research Institute, director of their [00:01:00] nutrition and metabolism center and a professor emeritus of biochemistry and molecular biology at the University of California Berkeley. Rhonda Patrick has a phd in biomedical science. Dr. Patrick is currently a postdoctoral fellow at Children's Hospital, Oakland Research Institute and Dr Ames lab. She currently conducts clinical trials looking at the effects of nutrients on metabolism, inflammation, DNA damage and aging. In February of 2014 she published [00:01:30] a paper in the Federation of American Societies for Experimental Biology Journal on how vitamin D regulates serotonin synthesis and how this relates to autism. In part one Bruce and Rondo described his triage theory for micronutrients in humans and their importance in health and aging. In part two they discussed public health risk factors, research funding models, and the future work they wish to do. Here is part two of Brad Swift's interview with Dr Ames [00:02:00] and Patrick. Speaker 4: Is there a discussion going on in public health community about this sort of important that Rhonda, that one, Speaker 5: I think that people are becoming more aware of the importance of micronutrient deficiencies in the u s population. We've got now these national health and examination surveys that people are doing, examining the levels of these essential vitamins and minerals. 70% of the populations not getting enough vitamin D, 45% [00:02:30] population is not getting enough magnesium, 60% not getting enough vitamin K, 25% is not getting enough vitamin CS, 60% not getting enough vitamin E and on and on, 90% not getting enough calcium testing. It's very difficult to get. So I think that with these surveys that are really coming out with these striking numbers on these micronutrient deficiencies in the population, I'm in the really widespread and with triage, the numbers that tell you may be wrong because the thinking short term instead of long term, really what you want to know Speaker 6: [00:03:00] is what level [inaudible] indeed to keep a maximum lifespan. And our paper discussed all at and uh, but I must say the nutrition community hasn't embraced it yet, but they will because we're showing it's true and we may need even more of certain things. But again, you don't want to overdo it. Okay. Speaker 4: So talk a little bit about risk factors in general. In health, a lot of people, as you were saying, are very obsessed with chemicals or so maybe their risk assessment is [00:03:30] misdirected. What do you think are the big health issues, the big health risks? Speaker 6: I think obesity is like smoking. Smoking is eight or 10 years off your life. Each cigarette takes 10 minutes off your life. I mean, it's a disaster and smoking levels are going down and down because people understand. Finally, there's still a lot of people smoke, but obesity is just as bad years of expensive diabetes and the costs can be used. [00:04:00] Whatever you look at out timers of brain dysfunction of all sites is higher in the obese and there's been several studies of the Diet of the obese and it's horrible. I mean it's sugar, it's comfort food and they're not eating fruits and vegetables and the not eating berries and nuts and not eating fish. And so it's doing the main and the country is painful. Speaker 5: I think that the biggest risk in becoming unhealthy and increasing your [00:04:30] risk of age related diseases, inflammatory diseases comes down to micronutrient intake and people are not getting enough of that. And we know that we quantified it, we know they're not getting enough. And so I think that people like to focus on a lot of what not eat, don't eat sugar and that's right. You shouldn't eat a lot of sugar. I mean there's a lot of bad effects on, you know, constantly having insulin signaling activated. You can become insulin resistant in type two diabetic and these things are important. But I think you also need to realize you need to focus on what you're not getting as opposed to only focusing on what you should not [00:05:00] be getting. Yeah, Speaker 6: a colleague, lowest scold, and I wrote over a hundred papers trying to put risk in perspective. That part to been in pesticide is really uninteresting. Organic food and regular food doesn't matter. It's makes you feel good, but you're really not either improving the environment or helping your health. Now that you're not allowed to say that, things like that in Berkeley. But anyway, it's your diet. You should be worried about getting a good balanced time. So if you put out a thousand [00:05:30] hypothetical risks, you're lost space. Nobody knows what's important anymore and that's where we're getting. Don't smoke and eat a good diet. You're way ahead of the game and exercise and exercise. Right.Speaker 4: And in talking about the current situation with funding, when you think back Bruce, in the early days of your career and the opportunities that were there for getting funding vastly Speaker 6: different. [00:06:00] Well, there was much less money in the system, but I always was able to get funded my whole career and I've always done reasonably well. But now it's a little discouraging when I think I have big ideas that are gonna really cut health care costs and we have big ideas on obesity and I just can't get any of this funded [inaudible] but now if you're an all original, it's hopeless putting it at grant, [00:06:30] I just have given up on it. Speaker 5: Well the ANA, the NIH doesn't like to fund. Speaker 6: Yeah. If you're thinking differently than everybody else you do and they're only funding eight or 9% of grants, you just can't get funded. I didn't want to work on a 1% so I'm funding it out of my own pocket with, I made some money from a biotech company of one my students and that's what's supporting my lamb and few rich people who saw potential gave me some money. But it's really tough [00:07:00] now getting enough money to do this. That's an interesting model. Self funding. Well, Rhonda is trying to do that with a, she has a blog and people supporting her in, Speaker 5: I'm trying to do some crowdfunding where instead of going to the government and then all these national institute of cancer, aging, whatever, which essentially uses taxpayer dollar anyways to fund research. I'm just going to the people, that's what I'm trying to do. My ultimate goal is to go to the people, tell them about this research I'm doing and [00:07:30] my ideas how we're going to do it and have them fund it. People are willing to give money to make advances in science. They just need to know about it. What did you tell him what your app is? So, so I have an app called found my fitness, which is the name of my platform where I basically break down science and nutrition and fitness to people and I explained to them mechanisms. I explained to them context, you know, because it's really hard to keep up with all these press releases and you're bombarded with and some of them are accurate and some aren't and most of the time you just have no idea what is going on. Speaker 5: It's very [00:08:00] difficult to sort of navigate through all that mess. So I have developed a platform called found my fitness where I'm trying to basically educate people by explaining and breaking down the science behind a lot of these different types of website. And it's an app, it's a website that's also an app can download on your iPhone called found my fitness. And I have short videos, youtube videos that I do where I talk about particular science topics or health nutrition topics. I also have a podcast where I talk about them. I'm interviewing other scientists in the field and things like that. And also I've got a news community site [00:08:30] where people can interact posts, new news, science stories or nutrition stories, whatever it is and people comment. So we're kind of building in community where people can interact and ask questions and Speaker 6: Rhonda makes a video every once in a while and puts it up on her website and she has people supporting at least some of this and she hopes to finally get enough money coming in. We'll support her research. Speaker 5: No, I think we're heading that way. I think that scientists are going to have to findSpeaker 6: new creative ways to fund their research. Uh, particularly if they have creative ideas [00:09:00] is, Bruce mentioned it because it's so competitive to get that less than 10% funding. The NIH doesn't really fun, really creative and risky, but it's, you need somebody who gets it. If when you put out a new idea, right, and if it's against conventional wisdom, which I'd like to do with the occasion arises, then it's almost impossible anyway. Speaker 4: Even with your reputation. Speaker 6: Yeah, it's hard. I've just given [00:09:30] up writing grants now. It's a huge amount of work and when they keep on getting turned down, even though I think these are wonderful ideas, luckily I can keep a basal level supporting the lab. I found a rich fellow who had an autistic grandkid guy named Jorgensen and he supported Rhonda and he supported her for a year and she was able to do all these things. Yeah, my age, I want to have [00:10:00] a lot of big ideas and I just like to get them out there anyway. We shouldn't complain. We're doing okay. Right. It's a very fulfilling job. There's nothing more fulfilling than doing science in my opinion. Yes. Speaker 7: You're listening to spectrum and k a Alex Berkley. Today's guests are Dr. Bruce Ames and Dr Rhonda Patrick of Children's Hospital Oakland Research Institute. [00:10:30] Oh, Speaker 4: the ames test. When you came up with that, was that, what was the process involved with?Speaker 6: Well, how do you devise that? Well, I was always half a geneticist and half a bio chemist and I thought you Taishan is really important. And nobody was testing new substances out there to see if there were mutagens. And so I thought it'd be nice to develop a simple, easy test in bacteria for doing that. That [00:11:00] was cheap and quick. And then I became interested in the relation of carcinogens to mutagens and so I was trying to convince people at the active forms of carcinogens were muted. There were other people in that area too, but I was an early enthusiastic for that idea and anyway, it's just came from my knowledge of two different fields, but that's a long time ago. I'm more excited about the brain now. The current stuff Speaker 4: doing obviously is it's more [00:11:30] exciting. Yeah. Do you both spend time paying attention to other areas of science? Speaker 6: I read an enormous amount and every 10 or 15 years I seem to change my feel of and follow off something that seems a little hotter than the other things and I've been reasonably successful at that, so that's what I liked to do. I am constantly Speaker 5: about all the latest research coming out. I mean, that's like pretty much all I do is I'm very excited about the new [00:12:00] field of epigenetics, where we're connecting what we eat, our lifestyle, how much stress we are under, how much exercise we do, how much sleep we get, how this is actually changing, methylation patterns, acetylation patterns. In our DNA and how that can change gene expression, turn on genes, turn off genes. I mean how this all relates to the way we age, how it relates to behavior, how it relates to us passing on behaviors to our children, grandchildren, you know, this is a field that's to me really exciting and something that I've spend quite a bit of time reading about. So for both of [00:12:30] you, what have been in the course of your career, the technologies, Speaker 6: the discoveries that have impacted your work the most? Well obviously understanding DNA and all the things it does was a huge advance for biology. And I was always half a geneticist, so I was hopping up and down when that Watson Crick paper came out and I gave it in the Journal club to all these distinguished biochemists and they said very speculative. [00:13:00] I said I was young script. I said, you guys be quiet. This is the paper of the century. And it made a huge difference. And there's been one advance after another. A lot of technical advances, little companies spring up, making your life easier and all of that. So it's been fun going through this. Speaker 5: I think, you know, in terms of my own research, which got me to where I'm at now, a lot of the, the technological advances in making transgenic mouse models, [00:13:30] knocking out certain genes, being able to manipulate, doing, inserting viral vectors with a specific gene and with a certain promoter on it and targeting it to a certain tissue so you can, you know, look specifically at what it's doing in that tissue or knock it out and what it's doing and that tissue. That for me is a, been a very useful technology that's helped me learn a lot. In addition, I like to do a lot of imaging. So these fluorescent proteins that we can, you know, you use to tag on, look at other proteins where they're located both tissue wise and also intracellularly inside the cell. Doing [00:14:00] that in real time. So there's now live cell imaging we can do and see things dynamically. Like for example, looking at Mitochondria and how they move and what they're doing in real time. Like that for me is also been really a useful technology and helping me understand Mitochondria. And how they function, dysfunction can occur. So I think a, those, those have been really important technologies for me. Speaker 6: And then computers change biology. Google made a huge difference. You can put two odd facts into Google and outcome Molly's paper. You'd spend years in a library [00:14:30] trying to figure all this stuff out. So Google really made theoretical biology possible. And I think this whole paper that Rhonda did, she couldn't have done it without Google. That's was the technology that opened it all up. This is so much literature and nobody can read all this and remember it all that we need the search. And so is this kind of a boom in theoretical biology? Well, [00:15:00] I wouldn't say there's a boom yet, but there's so much information out there that people haven't put together. Speaker 5: Yeah, people have been generating data over the years. There's tons of data out there and there's a lot of well done research that people haven't put together, connected the dots and made big picture understanding of complex things. So I think that there is an opening for that. And I do think that people will start to do that more and they are starting to do it more and more. Speaker 6: So in the past there really wasn't a theoretical biology that was certainly Darwin was [00:15:30] theoretical you could say and lots of people had big ideas in the unified fields, but it was rare. Speaker 5: I think we have more of an advantage in that we can provide mechanisms a little easier because we can read all this data. You know people like Darwin, they were doing theoretical work but they were also making observations. So what we're doing now is we're looking at observations other people have made and putting those together. Speaker 8: [00:16:00] [inaudible] and [inaudible] is a public affairs show on k a l x Berkeley. This is part two of a two part interview with Bruce Ames and Rhonda Patrick. Speaker 6: Are there, are other scientists active in the longevity field whose work you admire that you would love to collaborate with? [00:16:30] Well or associated with? Always collaborates. So science is both very collegial and very competitive. You think somebody might get their first. But one of the tricks I like in my lab is we have half a dozen really good people with different expertise and we sit around a table and discuss things and it's no one person can know all medicine. And so [00:17:00] anyways, that helps. Yeah. And it might be collaborating with this guy now because both of you contribute something that the other person doesn't have a technique or whatever. And in three years we might be competing with them, but that's why it's good to keep good relations with everybody. But business is the same way companies compete and collaborate. Yeah. Speaker 5: I, I personally am in terms of the field of longevity. Uh, I admire the work of Elizabeth Blackburn [00:17:30] who discovered, uh, won the Nobel prize for be playing a role in discovering the enzyme telomerase Speaker 6: that was done at Berkeley, by the way. Speaker 5: Yeah. And she's now a professor at UCLA. So I would be really excited to set up a collaboration with her. Speaker 6: Well, what are the lab's research plans going forward now? Uh, well, other than Ryan Reinders next two papers. Yeah. Rhonda has these papers to get out. And I'd like to get the whole business [00:18:00] of tuning up our metabolism on firmer ground, convince nutrition people who are expert in one particular environment or most people studied B six for their whole lives or study Niacin for their whole lives or magnesium. And I buy it at the experts in a particular field to think about triage and what protein do we measure that tells you you're short a not getting enough, the vulnerable ones and get that idea [00:18:30] out and do a few examples and convince people that RDA should be based on long term effects rather than short term. And then Rhonda and I were talking the other day and we both got excited about drugs. This money to be made. Speaker 6: So pharmaceutical companies compete on getting new and better drugs and they can be billion dollar drugs but nutrition, nobody can make money out of it. And so there, [00:19:00] do you want to do a clinical trial on Vitamin d the way you do with the drug? Food and drug wants a double blind randomized controlled clinical trial. That's the gold standard for drugs. But it's not for nutrition is nutrition. You have to measure if 20% of the population is low on vitamin D, you don't want to do a study where you don't measure who's low and who's high because otherwise it's designed to fail. So you have to measure [00:19:30] things. Now, vitamin D actually many more deficient, but a lot of vitamins, 10% of lower 20% is low and you can't just lump them in with all the people have enough and do a randomized on one clinical trial and think it's going to mean something without measuring something. Speaker 6: Rhonda has one of her videos on our website to [inaudible] all these doctors who saved the vitamins are useless. They're all based on clinical trials that are designed for drugs [00:20:00] and they don't measure anything. So you have to know who should deficient and then taking that amount of value and makes you sufficient. I think, uh, some interesting re ongoing research in our lab is also the cornea bar. Yeah. So yeah, Joyce mechanical amp is directing a project on the Corey bar. We were deciding how do you get vitamins and minerals into the poor and we made a little bar, which is kind of all the components of a Mediterranean diet that people [00:20:30] aren't getting enough vitamins and all the vitamins and minerals and fish oil and vitamin D and soluble fiber and insoluble fiber and plant polyphenols and we can raise everybody's HDL in a couple of weeks and this is the mass of people aren't eating, they think they're eating good tide aren't and obese people or have their metabolism all fouled up and you were even learning how to make progress there. So Speaker 5: cool thing about it is that you can take a population [00:21:00] of people that eats very unhealthy and they are obese, meaning they have a BMI of 30 or above and you can give them this nutritional bar that has a variety of micronutrients. It has essential fatty acids and some polyphenols fiber and give it to them twice a day on top of their crappy diet. You don't tell them to change your diet at all. It's like keep doing what you're doing, but here, eat those twice a day on top of what you're doing and you can see that, you know after a few weeks that these changes start to occur where their HDLs raise or LDS lower. I mean there's, there's a lot of positive effects, you know, lower c reactive protein. So [00:21:30] I think this is really groundbreaking research because it's, it says, look, you can take someone who's eating a terrible diet completely, probably micronutrient division in many essential vitamins and minerals and such are eating a bunch of sugar and crap and processed foods and on and on and on and yet you can give them this nutritional bar that has a combination of micronutrients in it and you can quantify changes that are positive. Speaker 5: I think that's a really exciting ongoing project in our lab, Speaker 6: Bruce Ames and Rhonda Patrick, thanks very much [00:22:00] for being on spectrum. It's a pleasure. Absolutely a pleasure. Thanks for having us. Speaker 7: Aw. [inaudible] to learn more about the work aims and Patrick's are doing. Visit their websites. Bruce seems.org and found my fitness.com spectrum shows are archived on iTunes yet we've created this simple link for you. The link is tiny url.com/k a Alex spectrum Speaker 3: [00:22:30] and now a calendar of the science and technology events happening locally over the next two weeks. Rick Kreisky joins me to present the calendar on Sunday July 13th the bay area meetup, random acts of science will host an event to do science with paper papers, one of the most commonly available materials with a variety of science applications. Everything from the dynamics of classic paper airplanes launching paper rockets and building structures in [00:23:00] Origami will be discussed. The group will also learn about fibers and paper and how to create their own homemade paper. Raw materials will be provided, but attendees are also welcome to bring their own. The event will be held July 13th from two to 3:00 PM outside the genetics and plant biology building on the UC Berkeley campus. It is free and open to anyone interested in coming basics. The Bay area art science, interdisciplinary collaborative sessions. [00:23:30] We'll have their fifth event on Monday the 14th from six 30 to 10:00 PM at the ODC theater, three one five three 17th street in San Francisco. Speaker 3: The theme is monsters. Professor John Haffer. Nick, we'll introduce the audience to a peracetic fly that turns European honey bees into zombies, author and translator, Eric Butler. We'll explain how literature and film have made the Vampire [00:24:00] a native of Eastern Europe into a naturalized American with a preference for the Golden State Marine biologist David McGuire. Well, disentangle the media fueled myth of the shark from its true nature and Kyle Taylor, senior scientist for the gluing plant project will show off plants that glow in the dark. Admission will be on a sliding scale from absolutely nothing. Up to 20 bucks. Visit basics.com for more info. [00:24:30] That's B double a s I c s.com. On Saturday, July 19th you see Berkeley molecular and cell biology Professor Kathleen Collins will host the latest iteration of the monthly lecture series. Signs that cow Professor Collins will discuss the connections between the seemingly incontrovertible fact of human aging. A fascinating enzyme known as telomerase and malignant cancers. Speaker 3: While cancer cells can grow indefinitely [00:25:00] all normally functioning human tissues will eventually die out. This is because with each success of cell division, the protective cap or a telomere at the end of each chromosome is gradually degraded while the enzyme to limb arrays or pairs this damage in embryos. It is not fully active in adult human tissues. Perhaps to prevent the uncontrollable growth of cancer cells. Professor Collins will discuss telomeres and telomerase function and how they affect the balance of human aging [00:25:30] and immortality. The free public talk will be held July 19th in room one 59 of Mulford Hall on the UC Berkeley campus. The lecture will begin at 11:00 AM sharp science need is a monthly science happy hour for adults 21 and over the pairs. Lightning talks with interactive stations on the back patio of the El Rio bar at three one five eight mission street in San Francisco. Speaker 3: [00:26:00] The theme for July Science Neat is backyard science and we'll feature the science of things right here in the bay area from plants to plankton and beetles. Two bikes. Admission is $4 and the event will be on Tuesday, July 22nd from six 30 to 8:30 PM and now a few of our favorite science stories. Rick's back to present the news. The rocky planets that are closest to our son generally have an iron core [00:26:30] that makes up about a third of their mass that is surrounded by rock that makes up the other two thirds. Mercury is an exception and is the other way around. With a massive iron core that takes up about percent of the planet's mass. This has been difficult to explain. If mercury had been built up by collisions the way that Venus and earth and Mars where we'd expect it to have a similar composition in a letter published in nature geoscience on July six Eric s [00:27:00] fog and Andreas Roofer of Arizona State University report their simulations that suggests that collisions may have stripped away Mercury's mantle, some moon and planet sized rocks would bounce off of each other, sometimes knocking one body out of its orbit while the impactor and the leftover debris coalesced into a planet. Speaker 3: This model is consistent with Mercury's high abundance of [inaudible] elements that have been observed recently by NASA's messenger spacecraft [00:27:30] in their so called hit and run model. Mercury is missing metal would end up coalescing onto Venus or in your report compiled by UC Berkeley. Scientist has definitively linkedin gene that has helped Tibetan populations thrive in high altitude environments to hit or too little known human ancestor. The Denisovans, the Denisovans along with any thoughts when extinct around 40 to 50,000 years ago about the time that modern human began to ascend [00:28:00] and Aaliyah is a version of a gene in this case and unusually of the gene e p a s one which regulates hemoglobin production has been common among Tibetans since their move several thousand years ago. John Habit areas at around 15,000 feet of elevation. Well, most people have Leos that caused them to develop thick blood at these high elevations, which can later lead to cardiovascular problems. The tobacco wheel raises hemoglobin levels only slightly allowing possessors [00:28:30] to avoid negative side effects. So the report, which will later republished in the journal Nature details the unique presence of the advantageous aliyah. Among Tibetans and conclusively matches it with the genome of the Denisovans. This is significant because as principle author, Rasmus Nielsen, UC Berkeley professor of integrative biology writes, it shows very clearly and directly that humans evolved and adapted to new environments by getting their genes from another species. Nielsen added that there are many other [00:29:00] potential species to explore as sources of human DNA Speaker 8: [inaudible].Speaker 4: This show marks the end of our production of spectrum. I want to thank Rick Karnofsky, Renee, Rau, and Alex Simon for their help in producing spectrum. I want to extend a blanket thank you to all the guests who took the time to appear on spectrum over the three years we have been on Calex to Sandra Lenna, [00:29:30] Erin and Lorraine. Thanks for your guidance and help to Joe, Peter and Greg. Thanks for your technical assistance and encouragement to listeners. Thanks for tuning in and Speaker 7: stay tuned to Calico [inaudible]. See acast.com/privacy for privacy and opt-out information.

Bruce Ames Sr Scientist at CHORI, and Prof Emeritus of Biochem and Molecular Bio, at UC Berkeley. Rhonda Patrick Ph.D. biomedical science, postdoc at CHORI in Dr. Ames lab. The effects of micronutrients on metabolism, inflammation, DNA damage, and aging.TranscriptSpeaker 1: Spectrum's next. Speaker 2: Okay. [inaudible] [inaudible]. Speaker 1: Welcome to spectrum the science and technology show [00:00:30] on k a l x Berkeley, a biweekly 30 minute program bringing you interviews featuring bay area scientists and technologists as well as a calendar of local events and news. Speaker 3: Hi there. My name is Renee Rao and I'll be hosting today's show this week on spectrum. We present part two of our two interviews with Bruce Ames and Rhonda Patrick. Dr Ames is a senior scientist at Children's Hospital, Oakland Research Institute, director of their [00:01:00] nutrition and metabolism center and a professor emeritus of biochemistry and molecular biology at the University of California Berkeley. Rhonda Patrick has a phd in biomedical science. Dr. Patrick is currently a postdoctoral fellow at Children's Hospital, Oakland Research Institute and Dr Ames lab. She currently conducts clinical trials looking at the effects of nutrients on metabolism, inflammation, DNA damage and aging. In February of 2014 she published [00:01:30] a paper in the Federation of American Societies for Experimental Biology Journal on how vitamin D regulates serotonin synthesis and how this relates to autism. In part one Bruce and Rondo described his triage theory for micronutrients in humans and their importance in health and aging. In part two they discussed public health risk factors, research funding models, and the future work they wish to do. Here is part two of Brad Swift's interview with Dr Ames [00:02:00] and Patrick. Speaker 4: Is there a discussion going on in public health community about this sort of important that Rhonda, that one, Speaker 5: I think that people are becoming more aware of the importance of micronutrient deficiencies in the u s population. We've got now these national health and examination surveys that people are doing, examining the levels of these essential vitamins and minerals. 70% of the populations not getting enough vitamin D, 45% [00:02:30] population is not getting enough magnesium, 60% not getting enough vitamin K, 25% is not getting enough vitamin CS, 60% not getting enough vitamin E and on and on, 90% not getting enough calcium testing. It's very difficult to get. So I think that with these surveys that are really coming out with these striking numbers on these micronutrient deficiencies in the population, I'm in the really widespread and with triage, the numbers that tell you may be wrong because the thinking short term instead of long term, really what you want to know Speaker 6: [00:03:00] is what level [inaudible] indeed to keep a maximum lifespan. And our paper discussed all at and uh, but I must say the nutrition community hasn't embraced it yet, but they will because we're showing it's true and we may need even more of certain things. But again, you don't want to overdo it. Okay. Speaker 4: So talk a little bit about risk factors in general. In health, a lot of people, as you were saying, are very obsessed with chemicals or so maybe their risk assessment is [00:03:30] misdirected. What do you think are the big health issues, the big health risks? Speaker 6: I think obesity is like smoking. Smoking is eight or 10 years off your life. Each cigarette takes 10 minutes off your life. I mean, it's a disaster and smoking levels are going down and down because people understand. Finally, there's still a lot of people smoke, but obesity is just as bad years of expensive diabetes and the costs can be used. [00:04:00] Whatever you look at out timers of brain dysfunction of all sites is higher in the obese and there's been several studies of the Diet of the obese and it's horrible. I mean it's sugar, it's comfort food and they're not eating fruits and vegetables and the not eating berries and nuts and not eating fish. And so it's doing the main and the country is painful. Speaker 5: I think that the biggest risk in becoming unhealthy and increasing your [00:04:30] risk of age related diseases, inflammatory diseases comes down to micronutrient intake and people are not getting enough of that. And we know that we quantified it, we know they're not getting enough. And so I think that people like to focus on a lot of what not eat, don't eat sugar and that's right. You shouldn't eat a lot of sugar. I mean there's a lot of bad effects on, you know, constantly having insulin signaling activated. You can become insulin resistant in type two diabetic and these things are important. But I think you also need to realize you need to focus on what you're not getting as opposed to only focusing on what you should not [00:05:00] be getting. Yeah, Speaker 6: a colleague, lowest scold, and I wrote over a hundred papers trying to put risk in perspective. That part to been in pesticide is really uninteresting. Organic food and regular food doesn't matter. It's makes you feel good, but you're really not either improving the environment or helping your health. Now that you're not allowed to say that, things like that in Berkeley. But anyway, it's your diet. You should be worried about getting a good balanced time. So if you put out a thousand [00:05:30] hypothetical risks, you're lost space. Nobody knows what's important anymore and that's where we're getting. Don't smoke and eat a good diet. You're way ahead of the game and exercise and exercise. Right.Speaker 4: And in talking about the current situation with funding, when you think back Bruce, in the early days of your career and the opportunities that were there for getting funding vastly Speaker 6: different. [00:06:00] Well, there was much less money in the system, but I always was able to get funded my whole career and I've always done reasonably well. But now it's a little discouraging when I think I have big ideas that are gonna really cut health care costs and we have big ideas on obesity and I just can't get any of this funded [inaudible] but now if you're an all original, it's hopeless putting it at grant, [00:06:30] I just have given up on it. Speaker 5: Well the ANA, the NIH doesn't like to fund. Speaker 6: Yeah. If you're thinking differently than everybody else you do and they're only funding eight or 9% of grants, you just can't get funded. I didn't want to work on a 1% so I'm funding it out of my own pocket with, I made some money from a biotech company of one my students and that's what's supporting my lamb and few rich people who saw potential gave me some money. But it's really tough [00:07:00] now getting enough money to do this. That's an interesting model. Self funding. Well, Rhonda is trying to do that with a, she has a blog and people supporting her in, Speaker 5: I'm trying to do some crowdfunding where instead of going to the government and then all these national institute of cancer, aging, whatever, which essentially uses taxpayer dollar anyways to fund research. I'm just going to the people, that's what I'm trying to do. My ultimate goal is to go to the people, tell them about this research I'm doing and [00:07:30] my ideas how we're going to do it and have them fund it. People are willing to give money to make advances in science. They just need to know about it. What did you tell him what your app is? So, so I have an app called found my fitness, which is the name of my platform where I basically break down science and nutrition and fitness to people and I explained to them mechanisms. I explained to them context, you know, because it's really hard to keep up with all these press releases and you're bombarded with and some of them are accurate and some aren't and most of the time you just have no idea what is going on. Speaker 5: It's very [00:08:00] difficult to sort of navigate through all that mess. So I have developed a platform called found my fitness where I'm trying to basically educate people by explaining and breaking down the science behind a lot of these different types of website. And it's an app, it's a website that's also an app can download on your iPhone called found my fitness. And I have short videos, youtube videos that I do where I talk about particular science topics or health nutrition topics. I also have a podcast where I talk about them. I'm interviewing other scientists in the field and things like that. And also I've got a news community site [00:08:30] where people can interact posts, new news, science stories or nutrition stories, whatever it is and people comment. So we're kind of building in community where people can interact and ask questions and Speaker 6: Rhonda makes a video every once in a while and puts it up on her website and she has people supporting at least some of this and she hopes to finally get enough money coming in. We'll support her research. Speaker 5: No, I think we're heading that way. I think that scientists are going to have to findSpeaker 6: new creative ways to fund their research. Uh, particularly if they have creative ideas [00:09:00] is, Bruce mentioned it because it's so competitive to get that less than 10% funding. The NIH doesn't really fun, really creative and risky, but it's, you need somebody who gets it. If when you put out a new idea, right, and if it's against conventional wisdom, which I'd like to do with the occasion arises, then it's almost impossible anyway. Speaker 4: Even with your reputation. Speaker 6: Yeah, it's hard. I've just given [00:09:30] up writing grants now. It's a huge amount of work and when they keep on getting turned down, even though I think these are wonderful ideas, luckily I can keep a basal level supporting the lab. I found a rich fellow who had an autistic grandkid guy named Jorgensen and he supported Rhonda and he supported her for a year and she was able to do all these things. Yeah, my age, I want to have [00:10:00] a lot of big ideas and I just like to get them out there anyway. We shouldn't complain. We're doing okay. Right. It's a very fulfilling job. There's nothing more fulfilling than doing science in my opinion. Yes. Speaker 7: You're listening to spectrum and k a Alex Berkley. Today's guests are Dr. Bruce Ames and Dr Rhonda Patrick of Children's Hospital Oakland Research Institute. [00:10:30] Oh, Speaker 4: the ames test. When you came up with that, was that, what was the process involved with?Speaker 6: Well, how do you devise that? Well, I was always half a geneticist and half a bio chemist and I thought you Taishan is really important. And nobody was testing new substances out there to see if there were mutagens. And so I thought it'd be nice to develop a simple, easy test in bacteria for doing that. That [00:11:00] was cheap and quick. And then I became interested in the relation of carcinogens to mutagens and so I was trying to convince people at the active forms of carcinogens were muted. There were other people in that area too, but I was an early enthusiastic for that idea and anyway, it's just came from my knowledge of two different fields, but that's a long time ago. I'm more excited about the brain now. The current stuff Speaker 4: doing obviously is it's more [00:11:30] exciting. Yeah. Do you both spend time paying attention to other areas of science? Speaker 6: I read an enormous amount and every 10 or 15 years I seem to change my feel of and follow off something that seems a little hotter than the other things and I've been reasonably successful at that, so that's what I liked to do. I am constantly Speaker 5: about all the latest research coming out. I mean, that's like pretty much all I do is I'm very excited about the new [00:12:00] field of epigenetics, where we're connecting what we eat, our lifestyle, how much stress we are under, how much exercise we do, how much sleep we get, how this is actually changing, methylation patterns, acetylation patterns. In our DNA and how that can change gene expression, turn on genes, turn off genes. I mean how this all relates to the way we age, how it relates to behavior, how it relates to us passing on behaviors to our children, grandchildren, you know, this is a field that's to me really exciting and something that I've spend quite a bit of time reading about. So for both of [00:12:30] you, what have been in the course of your career, the technologies, Speaker 6: the discoveries that have impacted your work the most? Well obviously understanding DNA and all the things it does was a huge advance for biology. And I was always half a geneticist, so I was hopping up and down when that Watson Crick paper came out and I gave it in the Journal club to all these distinguished biochemists and they said very speculative. [00:13:00] I said I was young script. I said, you guys be quiet. This is the paper of the century. And it made a huge difference. And there's been one advance after another. A lot of technical advances, little companies spring up, making your life easier and all of that. So it's been fun going through this. Speaker 5: I think, you know, in terms of my own research, which got me to where I'm at now, a lot of the, the technological advances in making transgenic mouse models, [00:13:30] knocking out certain genes, being able to manipulate, doing, inserting viral vectors with a specific gene and with a certain promoter on it and targeting it to a certain tissue so you can, you know, look specifically at what it's doing in that tissue or knock it out and what it's doing and that tissue. That for me is a, been a very useful technology that's helped me learn a lot. In addition, I like to do a lot of imaging. So these fluorescent proteins that we can, you know, you use to tag on, look at other proteins where they're located both tissue wise and also intracellularly inside the cell. Doing [00:14:00] that in real time. So there's now live cell imaging we can do and see things dynamically. Like for example, looking at Mitochondria and how they move and what they're doing in real time. Like that for me is also been really a useful technology and helping me understand Mitochondria. And how they function, dysfunction can occur. So I think a, those, those have been really important technologies for me. Speaker 6: And then computers change biology. Google made a huge difference. You can put two odd facts into Google and outcome Molly's paper. You'd spend years in a library [00:14:30] trying to figure all this stuff out. So Google really made theoretical biology possible. And I think this whole paper that Rhonda did, she couldn't have done it without Google. That's was the technology that opened it all up. This is so much literature and nobody can read all this and remember it all that we need the search. And so is this kind of a boom in theoretical biology? Well, [00:15:00] I wouldn't say there's a boom yet, but there's so much information out there that people haven't put together. Speaker 5: Yeah, people have been generating data over the years. There's tons of data out there and there's a lot of well done research that people haven't put together, connected the dots and made big picture understanding of complex things. So I think that there is an opening for that. And I do think that people will start to do that more and they are starting to do it more and more. Speaker 6: So in the past there really wasn't a theoretical biology that was certainly Darwin was [00:15:30] theoretical you could say and lots of people had big ideas in the unified fields, but it was rare. Speaker 5: I think we have more of an advantage in that we can provide mechanisms a little easier because we can read all this data. You know people like Darwin, they were doing theoretical work but they were also making observations. So what we're doing now is we're looking at observations other people have made and putting those together. Speaker 8: [00:16:00] [inaudible] and [inaudible] is a public affairs show on k a l x Berkeley. This is part two of a two part interview with Bruce Ames and Rhonda Patrick. Speaker 6: Are there, are other scientists active in the longevity field whose work you admire that you would love to collaborate with? [00:16:30] Well or associated with? Always collaborates. So science is both very collegial and very competitive. You think somebody might get their first. But one of the tricks I like in my lab is we have half a dozen really good people with different expertise and we sit around a table and discuss things and it's no one person can know all medicine. And so [00:17:00] anyways, that helps. Yeah. And it might be collaborating with this guy now because both of you contribute something that the other person doesn't have a technique or whatever. And in three years we might be competing with them, but that's why it's good to keep good relations with everybody. But business is the same way companies compete and collaborate. Yeah. Speaker 5: I, I personally am in terms of the field of longevity. Uh, I admire the work of Elizabeth Blackburn [00:17:30] who discovered, uh, won the Nobel prize for be playing a role in discovering the enzyme telomerase Speaker 6: that was done at Berkeley, by the way. Speaker 5: Yeah. And she's now a professor at UCLA. So I would be really excited to set up a collaboration with her. Speaker 6: Well, what are the lab's research plans going forward now? Uh, well, other than Ryan Reinders next two papers. Yeah. Rhonda has these papers to get out. And I'd like to get the whole business [00:18:00] of tuning up our metabolism on firmer ground, convince nutrition people who are expert in one particular environment or most people studied B six for their whole lives or study Niacin for their whole lives or magnesium. And I buy it at the experts in a particular field to think about triage and what protein do we measure that tells you you're short a not getting enough, the vulnerable ones and get that idea [00:18:30] out and do a few examples and convince people that RDA should be based on long term effects rather than short term. And then Rhonda and I were talking the other day and we both got excited about drugs. This money to be made. Speaker 6: So pharmaceutical companies compete on getting new and better drugs and they can be billion dollar drugs but nutrition, nobody can make money out of it. And so there, [00:19:00] do you want to do a clinical trial on Vitamin d the way you do with the drug? Food and drug wants a double blind randomized controlled clinical trial. That's the gold standard for drugs. But it's not for nutrition is nutrition. You have to measure if 20% of the population is low on vitamin D, you don't want to do a study where you don't measure who's low and who's high because otherwise it's designed to fail. So you have to measure [00:19:30] things. Now, vitamin D actually many more deficient, but a lot of vitamins, 10% of lower 20% is low and you can't just lump them in with all the people have enough and do a randomized on one clinical trial and think it's going to mean something without measuring something. Speaker 6: Rhonda has one of her videos on our website to [inaudible] all these doctors who saved the vitamins are useless. They're all based on clinical trials that are designed for drugs [00:20:00] and they don't measure anything. So you have to know who should deficient and then taking that amount of value and makes you sufficient. I think, uh, some interesting re ongoing research in our lab is also the cornea bar. Yeah. So yeah, Joyce mechanical amp is directing a project on the Corey bar. We were deciding how do you get vitamins and minerals into the poor and we made a little bar, which is kind of all the components of a Mediterranean diet that people [00:20:30] aren't getting enough vitamins and all the vitamins and minerals and fish oil and vitamin D and soluble fiber and insoluble fiber and plant polyphenols and we can raise everybody's HDL in a couple of weeks and this is the mass of people aren't eating, they think they're eating good tide aren't and obese people or have their metabolism all fouled up and you were even learning how to make progress there. So Speaker 5: cool thing about it is that you can take a population [00:21:00] of people that eats very unhealthy and they are obese, meaning they have a BMI of 30 or above and you can give them this nutritional bar that has a variety of micronutrients. It has essential fatty acids and some polyphenols fiber and give it to them twice a day on top of their crappy diet. You don't tell them to change your diet at all. It's like keep doing what you're doing, but here, eat those twice a day on top of what you're doing and you can see that, you know after a few weeks that these changes start to occur where their HDLs raise or LDS lower. I mean there's, there's a lot of positive effects, you know, lower c reactive protein. So [00:21:30] I think this is really groundbreaking research because it's, it says, look, you can take someone who's eating a terrible diet completely, probably micronutrient division in many essential vitamins and minerals and such are eating a bunch of sugar and crap and processed foods and on and on and on and yet you can give them this nutritional bar that has a combination of micronutrients in it and you can quantify changes that are positive. Speaker 5: I think that's a really exciting ongoing project in our lab, Speaker 6: Bruce Ames and Rhonda Patrick, thanks very much [00:22:00] for being on spectrum. It's a pleasure. Absolutely a pleasure. Thanks for having us. Speaker 7: Aw. [inaudible] to learn more about the work aims and Patrick's are doing. Visit their websites. Bruce seems.org and found my fitness.com spectrum shows are archived on iTunes yet we've created this simple link for you. The link is tiny url.com/k a Alex spectrum Speaker 3: [00:22:30] and now a calendar of the science and technology events happening locally over the next two weeks. Rick Kreisky joins me to present the calendar on Sunday July 13th the bay area meetup, random acts of science will host an event to do science with paper papers, one of the most commonly available materials with a variety of science applications. Everything from the dynamics of classic paper airplanes launching paper rockets and building structures in [00:23:00] Origami will be discussed. The group will also learn about fibers and paper and how to create their own homemade paper. Raw materials will be provided, but attendees are also welcome to bring their own. The event will be held July 13th from two to 3:00 PM outside the genetics and plant biology building on the UC Berkeley campus. It is free and open to anyone interested in coming basics. The Bay area art science, interdisciplinary collaborative sessions. [00:23:30] We'll have their fifth event on Monday the 14th from six 30 to 10:00 PM at the ODC theater, three one five three 17th street in San Francisco. Speaker 3: The theme is monsters. Professor John Haffer. Nick, we'll introduce the audience to a peracetic fly that turns European honey bees into zombies, author and translator, Eric Butler. We'll explain how literature and film have made the Vampire [00:24:00] a native of Eastern Europe into a naturalized American with a preference for the Golden State Marine biologist David McGuire. Well, disentangle the media fueled myth of the shark from its true nature and Kyle Taylor, senior scientist for the gluing plant project will show off plants that glow in the dark. Admission will be on a sliding scale from absolutely nothing. Up to 20 bucks. Visit basics.com for more info. [00:24:30] That's B double a s I c s.com. On Saturday, July 19th you see Berkeley molecular and cell biology Professor Kathleen Collins will host the latest iteration of the monthly lecture series. Signs that cow Professor Collins will discuss the connections between the seemingly incontrovertible fact of human aging. A fascinating enzyme known as telomerase and malignant cancers. Speaker 3: While cancer cells can grow indefinitely [00:25:00] all normally functioning human tissues will eventually die out. This is because with each success of cell division, the protective cap or a telomere at the end of each chromosome is gradually degraded while the enzyme to limb arrays or pairs this damage in embryos. It is not fully active in adult human tissues. Perhaps to prevent the uncontrollable growth of cancer cells. Professor Collins will discuss telomeres and telomerase function and how they affect the balance of human aging [00:25:30] and immortality. The free public talk will be held July 19th in room one 59 of Mulford Hall on the UC Berkeley campus. The lecture will begin at 11:00 AM sharp science need is a monthly science happy hour for adults 21 and over the pairs. Lightning talks with interactive stations on the back patio of the El Rio bar at three one five eight mission street in San Francisco. Speaker 3: [00:26:00] The theme for July Science Neat is backyard science and we'll feature the science of things right here in the bay area from plants to plankton and beetles. Two bikes. Admission is $4 and the event will be on Tuesday, July 22nd from six 30 to 8:30 PM and now a few of our favorite science stories. Rick's back to present the news. The rocky planets that are closest to our son generally have an iron core [00:26:30] that makes up about a third of their mass that is surrounded by rock that makes up the other two thirds. Mercury is an exception and is the other way around. With a massive iron core that takes up about percent of the planet's mass. This has been difficult to explain. If mercury had been built up by collisions the way that Venus and earth and Mars where we'd expect it to have a similar composition in a letter published in nature geoscience on July six Eric s [00:27:00] fog and Andreas Roofer of Arizona State University report their simulations that suggests that collisions may have stripped away Mercury's mantle, some moon and planet sized rocks would bounce off of each other, sometimes knocking one body out of its orbit while the impactor and the leftover debris coalesced into a planet. Speaker 3: This model is consistent with Mercury's high abundance of [inaudible] elements that have been observed recently by NASA's messenger spacecraft [00:27:30] in their so called hit and run model. Mercury is missing metal would end up coalescing onto Venus or in your report compiled by UC Berkeley. Scientist has definitively linkedin gene that has helped Tibetan populations thrive in high altitude environments to hit or too little known human ancestor. The Denisovans, the Denisovans along with any thoughts when extinct around 40 to 50,000 years ago about the time that modern human began to ascend [00:28:00] and Aaliyah is a version of a gene in this case and unusually of the gene e p a s one which regulates hemoglobin production has been common among Tibetans since their move several thousand years ago. John Habit areas at around 15,000 feet of elevation. Well, most people have Leos that caused them to develop thick blood at these high elevations, which can later lead to cardiovascular problems. The tobacco wheel raises hemoglobin levels only slightly allowing possessors [00:28:30] to avoid negative side effects. So the report, which will later republished in the journal Nature details the unique presence of the advantageous aliyah. Among Tibetans and conclusively matches it with the genome of the Denisovans. This is significant because as principle author, Rasmus Nielsen, UC Berkeley professor of integrative biology writes, it shows very clearly and directly that humans evolved and adapted to new environments by getting their genes from another species. Nielsen added that there are many other [00:29:00] potential species to explore as sources of human DNA Speaker 8: [inaudible].Speaker 4: This show marks the end of our production of spectrum. I want to thank Rick Karnofsky, Renee, Rau, and Alex Simon for their help in producing spectrum. I want to extend a blanket thank you to all the guests who took the time to appear on spectrum over the three years we have been on Calex to Sandra Lenna, [00:29:30] Erin and Lorraine. Thanks for your guidance and help to Joe, Peter and Greg. Thanks for your technical assistance and encouragement to listeners. Thanks for tuning in and Speaker 7: stay tuned to Calico [inaudible]. Hosted on Acast. See acast.com/privacy for more information.

In this work, techniques were developed and used to study the properties of molecules on a single-molecule level. Single-molecule techniques have the major advantage, that in contrast to ensemble measurements, they allow a detailed insight on the distribution and dynamics of single molecules without averaging over subpopulations. The use of Total Internal Reflection Fluorescence Microscopy (TIRFM) in combination with single-pair Förster Resonance Energy Transfer (spFRET) and Alternating Laser Excitation (ALEX) allows the identification of molecular-states by making quantitative measurements of distances in the Ångström range. The development of highly sensitive photon detectors and the use of versatile labeling techniques with photostable (synthetic or genetically-encoded) fluorophores, extended the application of TIRF microscopy to in vitro and live-cell experiments. Despite reducing the complexity of biological systems down to the single-molecule level, functions of individual molecules and interactions between them can be very sophisticated and challenging to analyze. Using information theory based methods, e.g. HMM, the dynamics extracted from single-molecule data was used to illuminate protein interactions and functions. The highly regulated process of gene transcription plays a central role in living organisms. The TATA-box Binding Protein (TBP) is a Transcription Factor (TF) that mediates the formation of the Pre-Initiation Complex (PIC). The lifetime of TBP at the promoter site is controlled by the Modulator of transcription 1 (Mot1), an essential TBP-associated ATPase involved in repression and in activation of transcription. Based on ensemble measurements, various models for the mechanism of Mot1 have been proposed. However, little is known about how Mot1 liberates TBP from DNA. Using TIRF microscopy, the conformation and interaction of Mot1 with the TBP/DNA complex were monitored by spFRET. In contrast to the current understanding of how Mot1 works, Mot1 bound to the TBP/DNA complex is not able to directly disrupt the TBP/DNA complexes by ATP hydrolysis. Instead, Mot1’s ATPase activity induces a conformational change in the complex. The nature of this changed, "primed", conformation is the change of the bending dynamics of the DNA. The results presented in this work suggest a model in which this primed conformation is a destabilized TBP/DNA complex. The interaction with an additional Mot1 molecule is required in order to liberate TBP from DNA. The effect of Mot1 on the DNA dynamics is TBP binding orientation specific. Mot1 effects on the DNA bending dynamics are strongest for molecules where TBP is bound in the inverted binding orientation. The specificity of Mot1’s regulation of DNA bending dynamics suggests that Mot1 preferably "primes" TBP bound in the inverted binding orientation. The mechanistic insight into the interaction of Mot1 with the TBP/DNA complex serves as a framework for understanding the role of Mot1 in gene up- and down-regulation. In a second project, the same single-molecule techniques were used to fabricate and evaluate self-assembled optically controllable, nanodevices. Based on the specificity of Watson-Crick base pairing, DNA was used as a scaffold to position different fluorophores with nanometer accuracy. The functionality of these nanodevices was expanded by making them optically addressable by incorporation of the switchable fluorescent protein Dronpa. Two functions have been demonstrated: Signal enhancement using Optical Lock-In Detection (OLID) and pH sensing in a live-cell environment.

Replication of the genome is strongly inhibited when high fidelity DNA polymerases encounter unrepaired DNA lesions, which can not be processed. The highly stringent active sites of these polymerases are unable to accommodate damaged bases and therefore DNA lesions block the replication fork progression. In order to overcome this problem, cells have evolved mechanisms for either repairing the damage, or synthesising past it with specially adapted polymerasases. Eukaryotic DNA polymerase eta (Pol eta), belonging to the Y-family of DNA polymerases, is outstanding in its ability to replicate through a variety of highly distorting DNA lesions such as cyclobutane pyrimidine dimers (CPDs), which are the main UV-induced lesions. Also cisplatin induced 1,2-d(GpG) adducts (Pt-GGs), which are formed in a typical cancer therapy with cisplatin can be processed by Pol eta. The bypass of such intrastrand crosslinks by high fidelity DNA polymerases is particularly difficult because two adjacent coding bases are simultaneously damaged. Thus, replication by Pol eta allows organisms to survive exposure to sunlight or, in the case of cisplatin, gives rise to resistances against cisplatin treatment. Mutations in the human POLH gene, encoding Pol eta, causes the variant form of xeroderma pigmentosum (XP V), characterized by the failure to copy through CPDs. This leads to strongly increased UV sensitivity and skin cancer predisposition. This thesis describes mechanistic investigations of the translesion synthesis (TLS) process by S. cerevisiae DNA Pol eta at atomic resolution, which were undertaken in collaboration with the Hopfner group. To study this process, cisplatin lesioned DNA had to be prepared first. Once this technique was established, the catalytic fragment of Pol eta was crystallized as ternary complex with incoming 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) and an primer - template DNA containing a site specific Pt-GG adduct. The first obtained structure shows the ddCTP positioned in a loosely bound conformation in the active site, hydrogen bonded to the templating base. Realizing the importance of the 3’ hydroxy group for positioning the NTP and the DNA correctly inside the polymerase, the complex was crystallized again with a 2’-deoxynucleoside 5’-triphosphate (dNTP). To prevent nucleotidyl transfer, primer strands which terminate at the 3’-end with a 2’,3’ dideoxy ribose were prepared by reverse DNA synthesis and used for cocrystallization. The resulting crystals diffracted typically to 3.1-3.3Å resolution at a synchrotron light source. A Pol eta specific arginine (Arg73 in yeast Pol eta) was identified for its importance to position the dNTP correctly in the active site and was shown to be necessary for lesion bypass. In contrast to the fixed preorientation of the dNTP in the active site, the damaged DNA is bound flexibly in a rather open DNA binding cleft. Nucleotidyl transfer requires a revolving of the DNA, energetically driven by hydrogen bonding of the templating base to the dNTP. For the 3’dG of the Pt-GG, this step is accomplished by bona fide Watson-Crick base pairs to dCTP and is biochemically efficient and accurate. In contrast, bypass of the 5’dG of the Pt-GG is less efficient and promiscuous for dCTP and dATP. Structurally, this can be attributed to misalignment of the templating 5’dG due to the rigid Pt crosslink. In cooperation with the Cramer group the structural reasons for the blockage of RNA Polymerase II (RNAP II) by the cisplatin lesion were elucidated. Using structural as well as biochemical methods it could be shown that stalling results from a translocation barrier that prevents delivery of the lesion to the active site. AMP misincorporation occurs at the barrier and also at an abasic site, suggesting that it arises from nontemplated synthesis according to an 'A-rule' known for DNA polymerases. RNAP II can bypass a cisplatin lesion that is artificially placed beyond the translocation barrier, even in the presence of a G A mismatch. Thus, the barrier prevents transcriptional mutagenesis.

Molecular recognition, programmability, self-assembling capabilites and biocompatibility are unique features of DNA. The basic approach of DNA nanotechnology is to exploit these properties in order to fabricate novel materials and structures on the nanometer scale. This cumulative dissertation deals with three aspects of this young research area: fast analysis, autonomous control of functional structures, and biocompatible autonomous delivery systems for nanoscale objects. 1. At low temperatures and under favorable buffer conditions, two complementary DNA strands will form a double-helical structure in which the bases of the two strands are paired according to the Watson-Crick rules: adenine bases bind with thymine bases, guanine bases with cytosine bases. The melting temperature TM of a DNA duplex is defined as the temperature at which half of the double strands are separated into single strands. The melting temperature can be calculated for DNA strands of known sequences under standard conditions. However, it has to be determined experimentally for strands of unknown sequences and for applications under extreme buffer conditions. A method for fast and reliable determination of DNA melting temperatures has been developed. Stable gradients of the denaturing agent formamide were generated by means of diffusion in a microfluidic setup. Formamide lowers the melting temperature of DNA and a given formamide concentration can be mapped to a corresponding virtual temperature along the formamide gradient. Differences in the length of complementary sequences of only one nucleotide as well as a single nucleotide mismatch can be detected with this method, which is of great interest for the detection of sequence mutations or variations such as single nucleotide polymorphisms (SNPs). 2. Knowledge of the stability of DNA duplexes is also of great importance for the construction of DNA-based nanostructures and devices. Conformational changes occuring in artificially generated DNA structures can be used to produce motion on the nanometer scale. Usually, DNA devices are driven by the manual addition of fuel molecules or by the periodic variation of buffer conditions. One prominent example of such a conformational change is the formation of the so-called i-motif, which is a folded four-stranded DNA structure characterized by noncanonical hemiprotonated cytosine-cytosine base-pairs. In order to achieve controlled autonomous motion, the oscillating pH-value of a chemical oscillator has been employed to drive the i-motif periodically through its conformational states. The experiments were conducted with the DNA switch in solution and attached to a solid substrate and constitute the first example of DNA-based devices driven autonomously by a chemical non-equilibrium reaction. 3. Finally, a DNA-crosslinked and switchable polyacrylamide hydrogel is introduced, which is used to trap and release fluorescent colloidal quantum dots in response to externally applied programmable DNA signal strands. Trapping and release of the nanoparticles is demonstrated by studying their diffusion properties using single molecule fluorescence microscopy, single particle tracking and fluorescence correlation spectroscopy. Due to the biocompatibility of the polymerized acrylamide and the crosslinking DNA strands, such gels could find application in the context of controlled drug delivery, where the autonomous release of a drug-carrying nanoparticle could be triggered by naturally occurring, potentially disease-related DNA or RNA strands.

Base pairing in natural oligonucleotides relies on hydrogen bonding and pi-stacking. Applying coordinative interactions between ligand-like nucleobases and metal cations is a new way of assembling artificial oligonucleotide duplexes. The incorporation of numerous metal-base pairs into oligonucleotides may lead to interesting compounds for nano-technological applications. In this thesis, the synthesis of the salen-metal base pair is described, which comprises preparation of a suitable protected salicylic aldehyde precursor and an organo-cuprate mediated C-glycosidation as the key step. An x-ray structure of the monomeric copper-salen base pair shows a very good geometrical match with natural Watson-Crick base pairs. Up to 10 consecutive salicylic aldehyde-nucleobases could be incorporated into DNA oligonucleotides by means of phosphoramidite chemistry. The synthesized double strands with one ligand show typical B-DNA CD-spectra and distinct melting characteristics. Addition of excess ethylenediamine and 1 eq of Mn2+ or Cu2+ increase the melting temp. by 28 °C and 42 °C, respectively. The complexation of these and other metals was examined by UV-, CD- and EPR-spectroscopy and high res. ESI mass spectrometry. It was possible to stack 10 manganese atoms inside the double helix and to prepare sequence specifically arrays of up to 5 copper ions plus 5 mercury ions inside one duplex.