POPULARITY
3 episodes with Functional genomics
3 episodes with Functional genomics
2 episodes with Functional genomics
2 episodes with Functional genomics
7 episodes with Functional genomics
2 episodes with Functional genomics
2 episodes with Functional genomics
2 episodes with Functional genomics
2 episodes with Functional genomics
Everyone's talking about nervous system regulation—but WTF does it actually mean? In this solo episode, Amanda Panacea breaks down what nervous system regulation really is (beyond the buzzwords), why so many people misunderstand it, and how to know if you're truly living from a regulated place—or just intellectualizing your healing. She shares: Why feeling safe is the foundation of healing (and how most people skip this step)How dysregulation shows up as overthinking, apathy, people-pleasing, burnout, and even compulsive “biohacking”What nervous system regulation actually feels like in real lifeHer personal journey from cognitive awareness to embodiment, and what changed everythingThe somatic channels of awareness you can start using right now—no special tools or routines requiredThis episode is for the high achievers, the overthinkers, the “I've done all the work but still feel stuck” crowd. If you've ever asked yourself “How do I actually feel my emotions?”—this one's for you.▶ Learn Amanda's 5-step nervous system method at feeltoheal.co▶ Join the monthly group for live coaching + guided regulation at just $50/month: https://l.bttr.to/e8XbZ▶ Join Amanda's 1:1 Transformation Coaching 3 month Container by booking a free 15 min call: https://l.bttr.to/cih5BCopywrite @AmandaPanacea Lets work together!· https://thehealerrevolution.com/ · Learn about my testing and coaching services: https://youtu.be/U7o17WErb84si=aaDZyp7txO6txtzm · Free 15 mins clarity call https://l.bttr.to/cih5BMy Most popular Courses, Guides, and Product Referrals· Product Links https://shopmy.us/amandapanacea· Feel to Heal: Transform Triggers into Calm (My signature course): https://feeltoheal.co/ · MCAS and histamine intolerance guide https://l.bttr.to/ivR0z· How to Heal MCAS and Histamine Intolerance Webinar: https://l.bttr.to/3Qnmv · HolyHydrogen Molecular Hydrogen: https://holyhydrogen.com/Panacea · King Coffee (Reishi spore infused organic coffee): https://thehealerrevolution.myorganogold.com/en/premium-gourmet-king-of-coffee/ Are you a practitioner, coach, or want to be? · Get certified in Bioenergetic testing: https://bioenergetics.learnworlds.com...· Learn HTMA and sign up for the HTMA app: https://hairanalysis.report/ref/165/ · Learn how to use and source Peptides (for non practitioners also!): https://amandapanacea--designergenes.thrivecart.com/pepsquad/ · Functional Genomics and Epigenetics: https://thedesignergenesco.com/bbd?affiliate=amandapanacea · Learn to read Mold labs and OAT: https://amandapanacea.krtra.com/t/4yQ7W1qjLT9cBuy my 365 day Somatic Manifestation Journal: https://www.amazon.com/dp/B0CQNSKXWD #AdrenalFatigue #anxietyrelief #bioenergetics #neuroscience #brainretraining #somatichealing #ChronicStress #hrv #functionalfreeze #AdrenalSupport #fightflightfreeze #nervoussytemregulation #nervoussystem #bloodsugar #anxiety #burnout #functionalmedicine #htma #bioenergetictesting #mcas #eczema #lyme #moldillness #gutbrainconnection #lymedisease #mastcellactivationsyndrome #tsw #topicalsteroidwithdrawal #guthealth #mineralbalancing #circadianrhythms #mastcellactivation #frequencyhealing #allergyrelief #weightloss #peptides #stressrelief #traumahealing #peptidesforweightloss #Bioenergetictesting
What if more people can change the way they die?In this episode, our hosts Dr. Krista Kostroman and Tracy Wood, dive into a discussion with Dr. Bianca Vega. Dr. Bianca is the CEO and Founder of Welli Biohacking and Wellness Clinic, the first and only biohacking and DNA testing clinic in Puerto Rico with the help of DNA Co. She is also a neuropsychologist and a biohacker who aims to bring hope to her clients. Learn more behind Dr. Bianca's motivations and vision for healthcare today!▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Keep yourself up to date on The DNA Talks Podcast! Follow our socials below:The DNA Talks Podcast Instagram https://www.instagram.com/dnatalkspodcast/▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Inspiring Motivational Background by Stock-Waveshttps://www.stock-waves.com/https://protunes.net/Video Link: https://www.youtube.com/watch?v=pbwVDTn-I0o&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fG&index=5▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Peaceful Corporate by Stock-Waveshttps://protunes.net/Video Link: https://www.youtube.com/watch?v=I34bTKW8ud0&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fGMedical Disclaimer: The information provided in this communication is for general informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read here. If you think you may have a medical emergency, call your doctor or 911 immediately.
MCAS, hypermobility, neurodivergence, & dysautonomia with Dr. Laura Gouge, ND, CNSIn this episode of The Healer Revolution, I sit down with Dr. Laura Gouge, ND, CNS, a naturopathic physician and expert in mast cell activation syndrome (MCAS), POTS, ADHD, long COVID, and nervous system dysregulation. We dive deep into the connections between immune function, histamine intolerance, neurodivergence, and chronic conditions like hypermobility, dysautonomia, and anxiety.Dr. Gouge shares her personal journey with MCAS, histamine intolerance and how she helps patients reduce sensitivities, regulate their nervous system, and reclaim their energy. We discuss why so many people with ADHD and anxiety also struggle with MCAS and how understanding these links can unlock deeper healing.If you've ever felt like your symptoms are all over the place—ranging from allergies and gut issues to joint pain and brain fog and burnout—this conversation is for you!
In this solo episode of The Healer Revolution podcast, I explore the often-overlooked chapter: *what happens after healing?* I share how staying in the same place—mentally, emotionally, or even physically—can subconsciously anchor you to your old identity of illness, and why moving to Thailand was a massive, intuitive leap toward freedom and expansion.This episode is especially for practitioners or aspiring healers who have turned their pain into purpose. I talk about the subtle but dangerous loop where success becomes entangled with always having something to heal or teach. If you've ever felt like you're stuck talking about the same imbalances, same symptoms, same stories—it may be time to zoom out and ask: *Who am I without the healing crisis?*I also get personal—sharing the specific German New Medicine conflict I was working through that impacted my fertility and endocrine system. I reveal the actual steps I took to resolve it, and why mindset and trauma work alone aren't always enough. Sometimes, you need *new emotional experiences*—in your relationships, your environment, and your choices—to fully shift.**Update:** I recorded this episode two months ago, and I'm happy to share that the symptoms tied to that conflict—ones I'd dealt with for years—*have not returned*. There's been zero sign of that program continuing to run, which speaks volumes to the power of this work.Traveling has only deepened this truth. From unexpected earthquakes to sudden moves and lost belongings—discomfort is inevitable. But when you have a solid foundation for how to move through big emotions, symptoms, or setbacks, *you don't collapse—you recalibrate*. That's exactly why I still use the tools I teach in [Feel2Heal.co](https://feel2heal.co) every single day. There hasn't been a single challenge where this work hasn't supported me through.If you're ready to step out of the healing loop and into your next chapter—this episode is for you.Copywrite @AmandaPanacea Lets work together!· https://thehealerrevolution.com/ · Learn about my testing and coaching services: https://youtu.be/U7o17WErb84si=aaDZyp7txO6txtzm · Free 15 mins clarity call https://l.bttr.to/cih5BMy Most popular Courses, Guides, and Product Referrals· Product Links https://shopmy.us/amandapanacea· Feel to Heal: Transform Triggers into Calm (My signature course): https://feeltoheal.co/ · MCAS and histamine intolerance guide https://l.bttr.to/ivR0z· How to Heal MCAS and Histamine Intolerance Webinar: https://l.bttr.to/3Qnmv · HolyHydrogen Molecular Hydrogen: https://holyhydrogen.com/Panacea · King Coffee (Reishi spore infused organic coffee): https://thehealerrevolution.myorganogold.com/en/premium-gourmet-king-of-coffee/ Are you a practitioner, coach, or want to be? · Get certified in Bioenergetic testing: https://bioenergetics.learnworlds.com...· Learn HTMA and sign up for the HTMA app: https://hairanalysis.report/ref/165/ · Learn how to use and source Peptides (for non practitioners also!): https://amandapanacea--designergenes.thrivecart.com/pepsquad/ · Functional Genomics and Epigenetics: https://thedesignergenesco.com/bbd?affiliate=amandapanacea · Learn to read Mold labs and OAT: https://amandapanacea.krtra.com/t/4yQ7W1qjLT9cBuy my 365 day Somatic Manifestation Journal: https://www.amazon.com/dp/B0CQNSKXWD #AdrenalFatigue #anxietyrelief #bioenergetics #neuroscience #brainretraining #somatichealing #ChronicStress #hrv #functionalfreeze #AdrenalSupport #fightflightfreeze #nervoussytemregulation #nervoussystem #bloodsugar #anxiety #burnout #functionalmedicine #htma #bioenergetictesting #mcas #eczema #lyme #moldillness #gutbrainconnection #lymedisease #mastcellactivationsyndrome #tsw #topicalsteroidwithdrawal #guthealth #mineralbalancing #circadianrhythms #mastcellactivation #frequencyhealing
About the Guest(s): Kashif Khan is a leading expert in functional genomics and the CEO of a pioneering health company that focuses on personalized health strategies through genetic insights. With a professional history rich in health innovation, Khan's work centers on understanding the human genome to optimize personal health, prevent diseases, and enhance longevity. He is acclaimed for his methodological approach to personalized medicine, which integrates genetic coaching, environmental influences, and lifestyle choices to improve individuals' overall well-being. Episode Summary: In this enthralling episode, host Trevor Houston welcomes Kashif Khan for an in-depth discussion about the transformative potential of functional genomics in personalized health. The conversation delves into how understanding one's genetic make-up can lead to more targeted and effective health and lifestyle choices. By decoding the body's instruction manual—the DNA—Khan reveals how we can optimize our time and resources specifically tailored to individual needs, potentially adding years to our life spans. Functional genomics, a specialized branch of genetics, zeros in on why certain diseases occur and how they can be prevented. Khan outlines the limitations of traditional medicine's diagnose-and-prescribe model and promotes a genomics-focused approach to identify root causes and personalize health interventions. He discusses how genetic testing sheds light on metabolic functions and environmental sensitivities, allowing individuals to make informed decisions about everything from nutrition and supplements to exercise regimes and stress management. The insights offered promise to revolutionize personal health management, making the path to longevity and wellness not only accessible but practical. Resources: Kashif Khan LinkedIn: https://www.linkedin.com/in/mrkashkhan/ Career Transition Summit: https://event.webinarjam.com/register/67/04404igv LinkedIn e-book: https://online.flippingbook.com/view/714118097/ Subscribe: https://podcasters.spotify.com/pod/show/who-ya-know-show Trevor Houston is a licensed financial professional offering insurance/financial products through various carriers. For more info visit http://cpwstrategies.com Chapters: (0:00) Understanding Functional Genomics for Personalized Health Solutions (6:32) Genetic Susceptibility to Mold and Environmental Toxins (8:41) Personalized Health Choices Through Genetic Insights (14:51) Genetics, Lifestyle Choices, and Longevity Potential (20:24) The Impact of Genetics on Diet and Health (24:38) The Flaws in Chronic Disease Management and Medication Dependency (29:11) Genetic Insights Transform Perceptions of ADHD and Personal Potential (41:06) Discovering Personal Purpose and Managing Anxiety in Careers (51:13) Understanding Hair Loss Causes and Solutions Through DNA Analysis (53:24) Exploring Genetic Health Insights with Kashif Khan
In this episode, Dr. Stephanie Nielsen is joined by Candice Barley whom you may know as a talented actress, producer, and photographer but beyond these professional titles, she is a mother and a patient advocate for women with breast implant illness. After feeling inferior without breasts, she got her first implants at 24 which gave her a boost at that time without knowing what is yet to come. Dr. Stephanie and Candice discuss the story of why Candice had gotten implants and from there on, Candice started facing health consequences. Candice started feeling fatigue, palpitations, anxiety, among other symptoms before nailing it that the root cause behind these health problems were her breast implants. She found out that she had breast implant inflammation, and immediately got explant surgery and total capsulectomy. From then on, everything changed, and Candice had dedicated her time to educating herself on detoxing protocols, non-toxic beauty, and the best healing modalities. She started sharing her life's story on her instagram page @olisticolife and started helping other women throughout their explant journey.If you wish to learn more from Candice Barley, you may do so on the following channels:Instagram: @olisticolife Book: Empowered Explant: Your Personal Advocacy Handbook for BII and Explant Surgery Website: olisticolife.comYou may also avail of a special discount on our DNA360 test by using the code "OLISTICOLIFE" on our website now!▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Keep yourself up to date on The DNA Talks Podcast! Follow our socials below:The DNA Talks Podcast Instagram https://www.instagram.com/dnatalkspodcast/Dr. Stephanie Nielsen's website https://www.wishinguwellness.com/▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Inspiring Motivational Background by Stock-Waveshttps://www.stock-waves.com/https://protunes.net/Video Link: https://www.youtube.com/watch?v=pbwVDTn-I0o&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fG&index=5▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Peaceful Corporate by Stock-Waveshttps://protunes.net/Video Link: https://www.youtube.com/watch?v=I34bTKW8ud0&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fGMedical Disclaimer: The information provided in this communication is for general informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read here. If you think you may have a medical emergency, call your doctor or 911 immediately.
Matters Microbial #61: All In Due Time–How Bacteria Wake from Dormancy October 17, 2024 Today, Dr. Paul Carini, of the Environmental Science department of the University of Arizona, joins the #QualityQuorum to discuss how soil bacteria can become dormant, “wake up,” and why that is more relevant than you might suppose. Host: Mark O. Martin Guest: Paul Carini Subscribe: Apple Podcasts, Spotify Become a patron of Matters Microbial! Links for this episode A lovely essay about the “Cultivation Conundrum”: why so many microbes in nature cannot be grown in the laboratory. The “uncultivated majority” is often called “microbial dark matter,” described here. An essay about the scale of microbiology with some fascinating facts. Arizona Culture Collection project by Dr. Carini and colleagues. Dilution to extinction technique An overview of sporulation, including some fascinating variations. A description of Arthrobacter A description of Bradyrhizobium An essay explaining PCA plots An essay about intrinsically disordered proteins A very nice video about working in Dr. Carini's lab. HIGHLY RECOMMENDED. Dr. Carini's faculty website. Dr. Carini's fascinating laboratory website. Dr. Carini's Substack page, where he explores many microbiological ideas. Intro music is by Reber Clark Send your questions and comments to mattersmicrobial@gmail.com
Do you ever get frustrated about doing everything that you know is healthy but still feeling your worst each day? That is exactly how Linda Craft felt before she decided it was about time that she got her DNA tested and some help from Lynn Angel who interpreted the results for her, and went through the journey of optimizing Linda's health with her.Discover the truth about your genetics and what lifestyle changes you must do in order to get to the root cause of all your symptoms! Learn from the story of Linda Craft, CEO and Founder of the Linda Craft Team Realtors, as she discusses how her relationship with health was from growing up until now where she feels her best!Tune in and get inspired to do the work to change the day you die!▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Keep yourself up to date on The DNA Talks Podcast! Follow our socials below:The DNA Talks Podcast Instagram https://www.instagram.com/dnatalkspodcast/Dr. Stephanie Nielsen's website https://www.wishinguwellness.com/Lynn Angel's website https://lynnangel.com/Tracy Wood's Official Instagram Account https://www.instagram.com/dnatracyofficial/Linda Craft's Social Links linktr.ee/lindacraftteam You may also watch this episode on YouTube.▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Grab your own DNA 360 test kit today!Our revolutionary DNA 360 Test is designed to dive into the secrets of your biological makeup. Unlike basic DNA tests, your DNA 360 reports offer personalized health recommendations tailored to actively prevent identified risks and take the guesswork out of living your healthiest life.▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Inspiring Motivational Background by Stock-Waveshttps://www.stock-waves.com/https://protunes.net/Video Link: https://www.youtube.com/watch?v=pbwVDTn-I0o&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fG&index=5▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Music: Peaceful Corporate by Stock-Waveshttps://protunes.net/Video Link: https://www.youtube.com/watch?v=I34bTKW8ud0&list=PLQtpqy3zeTGB7V5lkhkfBVaiZyrysv_fG▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬Medical Disclaimer: The information provided in this communication is for general informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read here. If you think you may have a medical emergency, call your doctor or 911 immediately.
In this episode, Dr. Rob Whitfield, a board-certified plastic surgeon, and Chelsie Ward, a detox program practitioner, discuss breast implant illness and the importance of detoxification and liver health. Dr. Whitfield highlights the impact of breast implant illness and the necessity of understanding how the body processes toxins for optimal health. Chelsie shares her personal experience with breast implant illness and the benefits of detoxification methods like infrared saunas. They emphasize the need for individualized health plans, genetic testing, and foundational health practices such as proper nutrition and detoxification to support recovery and overall wellness. Show Highlights Impact of Alcohol on Health (00:04:49) Chelsea explains how alcohol consumption affects the liver and overall detoxification processes. Microbial Imbalance and Alcohol (00:06:25) Alcohol's role in causing gut dysbiosis and its negative effects on detoxification efforts. Understanding Liver Function (00:09:14) Discussion on why normal blood work doesn't always reflect liver health and the need for detox. Functional Genomics and Testing (00:10:41) Exploration of advanced testing methods for assessing liver and overall health. Foundational Medicine (00:12:13) Importance of foundational health practices like nutrition and detoxification in overall wellness. Air Quality and Mycotoxins (00:19:25) Discussion on the importance of air quality and mycotoxins in relation to health and detoxification. Environmental Mold Exposure (00:22:45) The impact of mold in living environments and the necessity of remediation for health recovery. Detoxification Process (00:32:47) The development of detoxification processes in response to patient needs and ongoing health challenges. Saunas and Heavy Metals (00:34:42) The relationship between sauna use and heavy metal detoxification, particularly concerning breast implants. Connect with Dr. Whitfield: Podcast (https://podcasts.apple.com/gb/podcast/breast-implant-illness/id1678143554) Spotify (https://open.spotify.com/show/1SPDripbluZKYsC0rwrBdb?si=23ea2cd9f6734667) TikTok (https://www.tiktok.com/@drrobertwhitfield?_t=8oQyjO25X5i&_r=1) IG (https://www.instagram.com/breastimplantillnessexpert/) FB (https://www.facebook.com/DrRobertWhitfield) Linkedin (https://www.linkedin.com/in/dr-robert-whitfield-md-50775b10/) X.com (https://x.com/rjwhitfield?lang=en) Read this article (https://www.breastcancer.org/treatment/surgery/breast-reconstruction/types/implant-reconstruction/illness/breast-implant-illness) Shop Dr. Whitfield's Solutions (https://drrobssolutions.com) SHARP (https://www.harp.health) NVISN Labs (https://nvisnlabs.com/) Get access to Dr. Rob's Favorite Products below: Danger Coffee (https://dangercoffee.com/pages/mold-free-coffee?ref=ztvhyjg) - Use our link for mold-free coffee. JASPR Air Purifier (https://jaspr.co/)- Use code DRROB for the Jaspr Air Purifier. Echo Water (https://echowater.com/)- Get high-quality water with our code DRROB10. BallancerPro (https://ballancerpro.com) - Use code DRROBVIP for the world's leader in lymphatic drainage technology. Ultrahuman (https://www.ultrahuman.com/ring/buy/us/?affiliateCode=drwhitfield)- Use code WHITFIELD10 for the most accurate wearable.
In deze aflevering krijgen we een mini-college tumorcellen van Roderick Beijersbergen, professor in Functional Genomics en groepsleider op het Nederlands Kankerinstituut. Hij kijkt in zijn onderzoek hoe de behandelingen van verschillende soorten kanker verder verbeterd kunnen worden. Hoe blijf je al die soorten tumorcellen, die steeds maar weer slimme manieren verzinnen om resistent te worden tegen behandelingen, te slim af? Daarbij krijgen ze onder andere hulp van robots die gigantisch veel experimenten tegelijk kunnen doen.See omnystudio.com/listener for privacy information.
In deze aflevering krijgen we een mini-college tumorcellen van Roderick Beijersbergen, professor in Functional Genomics en groepsleider op het Nederlands Kankerinstituut. Hij kijkt in zijn onderzoek hoe de behandelingen van verschillende soorten kanker verder verbeterd kunnen worden.
First up this week, Staff Writer Adrian Cho talks with host Sarah Crespi about a fusion company that isn't aiming for net energy. Instead, it's looking to sell off the high-energy neutrons from its fusion reactors for different purposes, such as imaging machine parts and generating medical isotopes. In the long run, the company hopes to use money from these neutron-based enterprises for bigger, more energetic reactors that may someday make fusion energy. Next, we hear from Tian Du, a Ph.D. candidate in the Dr John and Anne Chong Lab for Functional Genomics at the University of Sydney. She talks about finding antivenom treatments by screening all the genes in the human genome. Her Science Translational Medicine paper focuses on a strong candidate for treating spitting cobra bites, but the technique may prove useful for many other venomous animal bites and stings, from jellyfish to spiders. This week's episode was produced with help from Podigy. About the Science Podcast Authors: Sarah Crespi, Adrian Cho Learn more about your ad choices. Visit megaphone.fm/adchoices
First up this week, Staff Writer Adrian Cho talks with host Sarah Crespi about a fusion company that isn't aiming for net energy. Instead, it's looking to sell off the high-energy neutrons from its fusion reactors for different purposes, such as imaging machine parts and generating medical isotopes. In the long run, the company hopes to use money from these neutron-based enterprises for bigger, more energetic reactors that may someday make fusion energy. Next, we hear from Tian Du, a Ph.D. candidate in the Dr John and Anne Chong Lab for Functional Genomics at the University of Sydney. She talks about finding antivenom treatments by screening all the genes in the human genome. Her Science Translational Medicine paper focuses on a strong candidate for treating spitting cobra bites, but the technique may prove useful for many other venomous animal bites and stings, from jellyfish to spiders. This week's episode was produced with help from Podigy. About the Science Podcast Authors: Sarah Crespi, Adrian Cho Learn more about your ad choices. Visit megaphone.fm/adchoices
Episode Highlights With Kash KhanWhy medical gaslighting is a real problem in medicine The real reason women and men aren't medically the same and why this is empowering Looking at what biology is broken and genetics vs the symptoms to get real answersFunctional genomics vs genetics and how to understand your genes in a way that benefits youWhy genes are not our destiny and how we can work with our genes for better resultsThe genes they look at that make the biggest functional differenceOnly 5% of the US is actually metabolically healthy right now The genetic factors that affect metabolism and hormonesHow functional genetics relates to chronic disease and inflammationWomen put an average of 500 chemicals on their bodies per dayIt takes an average of 26 seconds for something to get through the skin and into the bloodGeneral things we can all avoid for better healthInsights are useful, but data is useless without the personal experience sideLearning how to know what is wrong and how to fix it based on your genes Resources We MentionKash Khan - InstagramKash Khan - Roadmap to 100 program
We first interviewed Ben Cross five years ago, when he was the Head of Functional Genomics at Horizon Discovery, and we're delighted to welcome him back to the podcast as CTO of PhoreMost, an innovative target discovery company focused on drugging the undruggable. Ben caught us up on what he's learned over the last five years, including why failing fast isn't a viable strategy in drug discovery, and introduced us to PhoreMost's brand new molecular glue platform, GlueSeeker.
Welcome to episode 051 of Life Sciences 360.We welcome Howard McLeod, a distinguished expert in precision medicine and pharmacogenomics. Howard shares his profound journey into the world of personalized medicine, emphasizing the significant impact of individualized treatments on cancer patients. From groundbreaking gene discoveries to advising cutting-edge biotech companies, Howard's work underscores the value of targeted therapies and their potential to transform patient outcomes.Howard also discusses his current roles, including his position as the Center Director for Precision Medicine and Functional Genomics at Utah Tech and his advisory role in several companies. He shares insights into exciting projects aimed at improving drug response predictions and mental health treatments for university students through pharmacogenomics.Chapters 00:00 - Introduction and Guest Welcome01:00 - The Importance of Experimental Therapies02:00 - Career Inspiration and Key Moments04:00 - Mentors and Lessons Learned06:00 - Practical Applications of Research08:00 - Staying Grounded in Patient Care10:00 - Current Roles and Projects12:00 - Addressing Mental Health in Students14:00 - Integrating Technology in Medicine18:00 - Simplifying Complex Medical Information22:00 - Reflections on Technological Advancements26:00 - Embracing Change and New Challenges30:00 - Final Thoughts and Future Outlook36:00 - Closing Remarks and Contact InformationThis episode is a treasure trove of insights for anyone interested in precision medicine, pharmacogenomics, and the future of healthcare. Don't miss Howard McLeod's inspiring journey and the valuable lessons he shares!-----Links:*Dr. Howard McLeod LinkedIn ( https://www.linkedin.com/in/howard-mcleod-90866a12/)*Harsh Thakkar LinkedIn (https://www.linkedin.com/in/harshvthakkar/)*Listen to this episode on the go!
Ever wondered what's actually behind your chronic fatigue and constant low energy? Let's explore the transformative power of mitochondria with expert insights. In today's episode on Cellular Health Optimization, we'll dive into advanced strategies like bioregulators & Brown's gas to optimize your cellular energy production & learn practical steps to enhance mitochondrial function & boost overall vitality. Whether you face chronic health challenges or seek peak performance, understanding mitochondria & your overall cellular health is key to unlocking sustained energy & well-being. Meet our guest Dr. Tim Jackson, DPT, blends Orthopedic Rehabilitation expertise with Functional Medicine. A B.S. graduate of Wake Forest University, he offers telehealth services globally, focusing on digestive health, energy optimization, autoimmune disorders, and mold toxicity. Certified in Functional Genomics, he created the "Heal Your Hormones" bootcamp and contributed to Ameer Rosic's book. Featured in The Huffington Post and podcasts like "Bulletproof Executive" and “Ben Greenfield Fitness,” he advises on Wellness Mama's medical board, providing insights into diverse health concerns. Thank you to our partners Outliyr Biohacker's Peak Performance Shop: get exclusive discounts on cutting-edge health, wellness, & performance gear Ultimate Health Optimization Deals: a roundup article of all the best current deals on technology, supplements, systems and more Gain mental clarity, energy, motivation, and focus with the FREE Outliyr Nootropics Mini-Course The simple, guided, and actionable Outliyr Longevity Challenge helps you unlock your longevity potential, slow biological aging, and maximize your healthspan Key takeaways Mitochondria play a key role in sending danger signals to your body To improve sleep, intelligence, and speed, focus on your mitochondria Thyroid issues almost always come with adrenal gland issues Mitochondrial dysfunction often first appears in the brain and nervous system The brain holds 9-10% of the body's mitochondria The main protectors of mitochondria are glutathione and superoxide dismutase Without phosphatidylcholine, we can't make bile or detoxify Detox and sleep are energy-intensive; many can't heal due to energy deficits Glutathione is a strong antiviral and immune modulator Links Watch it on YouTube: https://youtu.be/QEqSk2ftTSA Full episode show notes: mindbodypeak.com/162 Connect with Nick on social media Instagram Twitter YouTube LinkedIn Easy ways to support Subscribe Leave an Apple Podcast review Suggest a guest Do you have questions, thoughts, or feedback for us? Let me know in the show notes above and one of us will get back to you! Be an Outliyr, Nick
In this episode, Ayesha spoke with Howard McLeod, PharmD, Director of the Center for Precision Medicine and Functional Genomics, Professor of Pharmacy and Medicine at Utah Tech University and Precision Medicine Advisor at the Geriatric Oncology Consortium; and Sharmeen Roy, PharmD, Chief Strategy and Science Officer at DoseMe, which is the world's first and largest Bayesian dosing platform designed for clinical practice.Precision dosing, also known as personalized dosing, aims to tailor drug dosages to the individual characteristics of each patient to achieve optimal therapeutic outcomes while minimizing adverse effects. It leverages various patient-specific factors, including genetics, age, weight, organ function and even lifestyle, to determine the most appropriate dosage for each individual. Dr. McLeod is an internationally recognized expert in precision medicine, who has made novel contributions at the discovery, translation, implementation and policy levels. Dr. McLeod received his Doctorate in Pharmacy from the Philadelphia College of Pharmacy and Science and completed his Post-Doctoral Training at St Jude Children's Research Hospital and the University of Glasgow. Dr. Roy is passionate about leveraging technology to amplify the impact of the pharmacist. Her career spans pediatric clinical pharmacy, clinical research and pharmacogenomics with leadership roles at University of Chicago Medical Center and PipelineRx. She received her Doctor of Pharmacy degree from the University of Illinois at Chicago, is a Board-Certified Pharmacotherapy Specialist and completed a Pediatric Specialty Pharmacotherapy Residency at Texas Children's Hospital.Tune into the episode to learn more about the current landscape of precision dosing, including the latest technologies and tools designed to help optimize drug dosages.For more life science and medical device content, visit the Xtalks Vitals homepage. https://xtalks.com/vitals/ Follow Us on Social MediaTwitter: https://twitter.com/Xtalks Instagram: https://www.instagram.com/xtalks/ Facebook: https://www.facebook.com/Xtalks.Webinars/ LinkedIn: https://www.linkedin.com/company/xtalks-webconferences YouTube: https://www.youtube.com/c/XtalksWebinars/featured
Genetics is the transcript of your own personal health. We often perceive it as something that dictates that health issues are hereditary but the truth is that no one was born with chronic illnesses. In what way should we then perceive and interpret genetics?In this episode, Dr. Krista Kostroman is joined by Dr. Mansoor Mohammed, PhD. Dr. Mansoor is one of the founding members of The DNA Company as he had committed his life into studying genetics and all fields that revolve around it. He is a recognized authority in the fields of medical genomics and personalized medicine. He is the holder of several patents in the general fields of molecular diagnostics and genomics research. Dr. Mohammed completed his doctoral dissertation at the University of Guelph, Canada, majoring in both Molecular Immunology and Transgenic Technologies. He completed postdoctoral training in Clinical Cytogenetics at both UCLA and Baylor College of Medicine.Prior to becoming the scientific founder of The DNA Company, Dr. Mohammed co-founded Younique Genomics, served as the President and CEO of CombiMatrix Diagnostics—where he oversaw the development of one of the most comprehensive genomics testing menus in the diagnostic industry—and was the Director of Advanced Technologies at Quest Diagnostics, where he was honored with the Medical Innovation Award, the highest accolade given for excellence in medical research. Prior to his role at Quest Diagnostics, Dr. Mohammed was a founder and Director of Research and Development at Spectral Genomics. At Spectral Genomics, Dr. Mohammed pioneered the development of commercial Comparative Genomic Hybridization (CGH) array technologies and was responsible for the design and launch of the industry's first commercially available CGH arrays.Together, Dr. Krista and Dr. Mansoor go through the different stages and understandings of DNA that Dr. Mansoor went through - calling this the four epochs of his career.During the first epoch, Dr. Mansoor invented this whole genome technology where he studied human antibodies, and looked into animal models in order to deepen the study on the human's genetic makeup. This led him to founding companies such as Spectral Genomics and with the knowledge that they had at that time, they were able to focus on what was broken with the human body and used the study of DNA to find solutions to this. Moving on to 2011, he entered the second epoch of his career where he was questioned why they do not delve further than what was broken. This initiated Dr. Mansoor to dive deeper and study genomics with the addition of functional genomics. After continually studying what is unknown regarding a person's genomics, then comes the birth of The DNA Company. This story showcases how our clinicians today are able to prevent any possible illness by looking into a person's unique genetic makeup - even down to the body's smallest nuances.Onto the third epoch, the amount of information gathered must be handled with care so as not to dilute it in a soundbite that suggests that science is binary but rather give science its due right. This was when he realized that there was more to be done and stepped away to focus on studying yet continually serving people.Lastly, the fourth epoch dives into the study of hormone replacement and the continuous journey of advocating and researching for optimal human health, nutrition, lifestyle, and environment. ▬▬▬▬▬▬▬▬▬▬Keep yourself up to date on The DNA Talks Podcast! The DNA Talks Podcast Instagram https://www.instagram.com/dnatalkspodcast/Dr. Krista Kostroman's Official Instagram Page https://www.instagram.com/drkostromanofficial/This episode may also be viewed on YouTube
Welcome to Episode 185 of Autism Parenting Secrets.Today, we are returning to the topic of functional genomics. How better understanding your genes can inform lifestyle changes that can make a huge positive impact for you, your child, and your entire family.My guest is Kashif Khan, CEO of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome.Kashif was a keynote speaker at this year's Biohacking Conference in Orlando, Florida, and he truly has a fresh take on how you, the parent, can make better-informed choices to fill your own tank and to help your child on the spectrum thrive.The secret this week is…SIMPLE Habits Fix Genetic GapsYou'll Discover:What Exactly Are Epigenetics And Why Do They Matter So Much (8:05)Why Most Genetic Tests Aren't Designed To Help You (11:29)Why It's Essential To Understand Your Child's Genetic Makeup (19:48)The Difference Between Genetics and Functional Genomics (23:17)Three Ways To Look At Methylation (30:21)The Interplay Of Vitamin D And Genetics (36:17)The Six Steps To Develop The Right Habits (43:48)About Our GuestKashif Khan is Chief Executive Officer and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. He is also the host of the Unpilled podcast. Growing up in Vancouver, Canada in an immigrant household, Kashif developed an industrious entrepreneurial spirit from a young age. Prior to his tenure at the DNA Company, Kashif advised a number of high-growth start-ups in a variety of industries. As Kashif dove into the field of functional genomics, it was revealed that his neural wiring was actually genetically designed to be entrepreneurial. However, his genes also revealed a particular sensitivity to pollutants. Now seeing his health from a new lens, Kashif dove further and started to see the genetic pathways that led to his own family's challenges and the opportunities to reverse chronic disease. His measure of success is not in dollars earned but in lives improved.The DNA CompanyReferences in The Episode:The DNA Way by Kashif Khan and Dave AspreyTiny Habits by B.J. FoggAdditional Resources:Take The Quiz: What's YOUR Top Autism Parenting Blindspot?To learn more about Cass & Len, visit us at www.autismparentingsecrets.comBe sure to follow Cass & Len on Instagram
Episode Description: Dive deep into the transformative world of biotechnology as we explore the potential of genetic variants, the future of food engineering, and the controversies surrounding GMOs. Kevin Folta sheds light on the power of genome sequences in predicting health predispositions and the revolutionary changes in the agricultural sector. From understanding the essence of tasteless tomatoes to the challenges of science communication, we unravel the intricacies of biotech and its profound impact on our daily lives. Grow Everything brings to life the bioeconomy when hosts Karl Schmieder and Erum Azeez Khan share stories from the field and interview leaders and influencers in the space. Life is a powerful force and it can be engineered. What are we creating? Learn more at www.messaginglab.com/groweverything Topics Covered: 00:00:00 Diving into the Biotech World: A Journey of Discovery and Debate 00:05:56 The Rise of Biotech: Startups and Innovations Leading the Charge 00:09:03 Celebrating Biotech Success: How Perfect Day Triumphed in Science Communication 00:12:07 Meet Kevin Folta: Exploring the Controversies and Knowledge in Biotechnology 00:15:50 Missteps in Science: How Threats and Misunderstandings Impact Careers 00:18:50 Debunking Myths: Addressing GMO Misconceptions and Vaccine Skepticism 00:20:22 Bridging the Gap: Engaging Non-Scientists through Biotech Education 00:23:22 Biotech Breakthroughs: From Nutbreeding to Next-Gen Applications 00:28:43 Clarifying GMOs: Addressing Common Misunderstandings 00:29:20 Shedding Light on GMOs: Separating Facts from Fiction 00:34:28 Plant Genetics Evolution: The Role of Functional Genomics in Breeding 00:37:02 Taste Rediscovered: The Garden Gem Tomato's Unique Flavor Profile 00:41:25 Nutritional Powerhouses: The Potential of the Purple Potato 00:46:21 Building Bridges: Advocating for Genetic Engineering Through Shared Values 00:48:39 Predictive Biotech: Personalized Medicine and Decoding Genetic Variants 00:50:38 Effective Science Communication: Strategies and Approaches 00:57:00 Navigating Biotech Narratives: Overcoming Misinformation and Creating Compelling Stories Episode Links: University of Florida LinkedIn GMO Answers Talking Biotech Podcast Articles at Genetic Literacy Project Articles on Medium Illumination 2.0 Blog Arcaea - Future Society (Company ) Jasmina Aganovic(Grow Everything Episode) Normal Phenomena of Life (Company) iGEM (Organization) Perfect Day's narrative (Company) Genetic Literacy Project (Organization) Have a question or comment? Message us here: Text or Call (804) 505-5553 Instagram / TikTok / Twitter / LinkedIn / Youtube / GrowEverything website Email: groweverything@messaginglab.com Support here: Patreon Music by: Nihilore Production by: Amplafy Media --- Send in a voice message: https://podcasters.spotify.com/pod/show/messaginglab/message
In episode 54 of C60 Health Connections, we deep dive into the world of genetic testing with Kashif Khan, Founder & CEO of The DNA Company. If you are even the slightest bit interested in optimizing your health this year, you do not want to miss the secrets revealed in is fascinating conversation! Kashif Khan is the author of The DNA Way, a two-time TEDx Speaker, and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. He is also the host of the Unpilled podcast. Growing up in Vancouver, Canada in an immigrant household, Kashif developed an industrious entrepreneurial spirit from a young age. Prior to his tenure at the DNA Company, Kashif advised a number of high-growth start-ups in a variety of industries. As Kashif dove into the field of functional genomics as the CEO of The DNA Company, it was revealed that his neural wiring was actually genetically designed to be entrepreneurial. However, his genes also revealed a particular sensitivity to pollutants. Now seeing his health from a new lens Kashif dove further and started to see the genetic pathways that led to his own family's challenges, and the opportunities to reverse chronic disease. His measurement of success is not in dollars earned, but in lives improved. Learn more about Kashif and the work he does at: https://www.thednacompany.com/ Follow Kashif on Instagram: @kashkhanofficial and @dnaco Check out his podcast here: https://www.thednacompany.com/blogs/u... Subscribe to his YouTube channel: / @thednacompany4669 And get 15% OFF your DNA test when you use this link: thednacompany.com/purplepower (We are not an affiliate for the DNA Company) Use the Coupon Code: THEC60SHOW for 10% off your first #Carbon60 order at: https://shopc60.com Check out the research studies here: https://shopc60.com/research, and here https://whatisc60.org Visit us on social media! Facebook - https://www.facebook.com/c60purplepow... Instagram - https://www.instagram.com/c60purplepo... Twitter - https://twitter.com/c60purplepower Search for us (“C60 Purple Power”) on any of your favorite alternative social media channels, too! Disclaimer: These statements and products have not been evaluated by the Food and Drug Administration. The information on this show, and C60 Purple Power products, are not intended to diagnose, treat, cure, mitigate, or prevent disease. Please consult a healthcare professional before starting any new diet or exercise regimen. Individual results may vary.
This episode will challenge the notion that genetics determines our health outcomes and shed light on the role of lifestyle factors in shaping our well-being. From debunking the claim that obesity is primarily genetic to uncovering genetic imbalances and finding effective solutions, this episode will leave you inspired and empowered to take control of your own health. Kashif Khan is an author, speaker, visionary entrepreneur and investor. He is the Chief Executive Officer and Founder of The DNA Company, a digital health company that uses genetic insights to develop genomics-based health management applications that offer patients precision healthcare tailored to their unique biology. In his newest title, The DNA Way: Unlock the Secrets of Your Genes to Reverse Disease, Slow Aging, and Achieve Optimal Wellness (May 16, 2023 / Hay House), Kashif gives an action plan based on your unique genetic makeup to help you live your best life. Key Topics: - What is functional genomics and how does it impact health? - Debunking the claim that obesity is genetic - Why Ozempic is not the best option for weight loss - The toxic pollutants harming your health - Reversing chronic disease with genomics - How Khan healed his niece's anxiety with genomics - How to work with systems Learn more at thednacompany.com, follow Kashif on instagram at @kashkhanofficial and find his book The DNA Way anywhere you buy books! Grab Erin's FREE high protein breakfast recipe pack here: https://mailchi.mp/a793b6756b9b/high-protein-breakfast-ideas Buy Erin's kids' recipe book here: https://www.amazon.com/Brain-Food-Whole-Family-Kid-Friendly/dp/B0C2S6B5B6
This episode will challenge the notion that genetics determines our health outcomes and shed light on the role of lifestyle factors in shaping our well-being. From debunking the claim that obesity is primarily genetic to uncovering genetic imbalances and finding effective solutions, this episode will leave you inspired and empowered to take control of your own health. Kashif Khan is an author, speaker, visionary entrepreneur and investor. He is the Chief Executive Officer and Founder of The DNA Company, a digital health company that uses genetic insights to develop genomics-based health management applications that offer patients precision healthcare tailored to their unique biology. In his newest title, The DNA Way: Unlock the Secrets of Your Genes to Reverse Disease, Slow Aging, and Achieve Optimal Wellness (May 16, 2023 / Hay House), Kashif gives an action plan based on your unique genetic makeup to help you live your best life. Key Topics: - What is functional genomics and how does it impact health? - Debunking the claim that obesity is genetic - Why Ozempic is not the best option for weight loss - The toxic pollutants harming your health - Reversing chronic disease with genomics - How Khan healed his niece's anxiety with genomics - How to work with systems Learn more at thednacompany.com, follow Kashif on instagram at @kashkhanofficial and find his book The DNA Way anywhere you buy books! Grab Erin's FREE high protein breakfast recipe pack here: https://mailchi.mp/a793b6756b9b/high-protein-breakfast-ideas Buy Erin's kids' recipe book here: https://www.amazon.com/Brain-Food-Whole-Family-Kid-Friendly/dp/B0C2S6B5B6
Episode 155. What Functional Genomics Can Tell You About Your Health with Kashif Khan - In this week's interview, my special guest Kashif Khan, Biomedical Explorer and Founder of The DNA Company, reviews my own DNA results to show you what you can learn about your health by getting yourself tested. We focused on areas of interest to women in midlife, but this particular test can guide you in better understanding your unique needs for: Diet & Nutrition Hormone, Fitness & Body TypeLongevity Sleep CardiovascularMood & BehaviourAnti-Inflammatory profile WANT TO GET TESTED? GET 10% OFF YOUR TEST KIT HERE = https://www.naturallyjoyous.ca/dna WATCH IT ON YOUTUBE = https://youtu.be/VVgD0RuDuBLEAVE US A REVIEW HERE & HELP SUPPORT OUT SHOWGET BACK IN CONTROL OF YOUR WEIGHT AFTER 40 FREE TRAININGWORK WITH US - BOOK YOUR COMPLIMENTARY RELEASE EPIPHANY SESSION HEREAbout Kashif Khan…Kashif Khan is Chief Executive Officer and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. He is also the host of the Unpilled podcast. Growing up in Vancouver, Canada in an immigrant household, Kashif developed an industrious entrepreneurial spirit from a young age. Prior to his tenure at the DNA Company, Kashif advised a number of high-growth start-ups in a variety of industries. As Kashif dove into the field of functional genomics as the CEO of The DNA Company, it was revealed that his neural wiring was actually genetically designed to be entrepreneurial. However, his genes also revealed a particular sensitivity to pollutants. Now seeing his health from a new lens Kashif dove further and started to see the genetic pathways that led to his own family's challenges, and the opportunities to reverse chronic disease. His measure of success is not in dollars earned, but in lives improved. Here is where you can find him:Get Kashif's book, The DNA Way= www.thednaway.comIf you enjoyed today's episode, please:Post a screenshot & key takeaway on your Instagram story and tag us @naturally.joyous so we can repost you Leave us a positive review on Apple Podcasts, HERE is howSubscribe to the Confidence From Within Podcast, we release new episodes every Friday! Hosted on Acast. See acast.com/privacy for more information.
EPISODE 119: Your health largely depends on your genetics, and those are set in stone. So if you're predisposed to Alzheimer's or cancer, there's nothing you can do, right? Wrong! There is a link between our genes and environmental health that, if we know how to leverage it, can significantly improve our health and help us prevent what we have long believed to be inevitable. Today's guest, the renowned longevity expert Kashif Kahn, is here to tell us all about it! Kashif is the founder and CEO of The DNA Company, a healthcare company pioneering personalized medicine through unique insights into the human genome. He is also the author of The DNA WAY and an official TEDx speaker. In this episode, we discuss functional genomics, personalized medicine, environmental health, and hormonal imbalances. Tune in! Key Takeaways: Intro (00:00) What is functional genomics? (01:00) Female hormone health (04:25) 7 key areas everyone needs to understand (13:18) Environmental hazards (17:17) Functional genomics and mental health (20:47) Lifestyle changes Kashif made to transform his health (27:05) Kashif's book The DNA WAY (31:58) Should you get your DNA checked? (36:48) DNA, data, and technology (42:50) Kashif on longevity (50:16) Outro (54:29) Additional Resources: ➡️ Take the next step to boosting your longevity: http://LLInsider.com/ ➡️ Coaching with Claudia: https://longevity-and-lifestyle.com/contact ➡️ Full list of resources, links, and show notes: https://longevity-and-lifestyle.com/podcast-119-kashif-khan Follow Kashif Khan: ✨ Website: https://www.thednacompany.com/ ✨ LinkedIn: https://ca.linkedin.com/in/mrkashkhan ✨ Instagram: https://www.instagram.com/kashkhanofficial/?hl=en ✨ Facebook: https://www.facebook.com/thednacompany Follow Claudia on social media: ✨ Facebook: https://www.facebook.com/claudiavonB ✨ Instagram: https://www.instagram.com/longevityandlifestyle/ ✨ LinkedIn: https://www.linkedin.com/in/claudia-von-boeselager/ ✨ Twitter: https://twitter.com/longevitylifest ✨ TikTok: https://www.tiktok.com/@longevityandlifestyle Follow The Longevity and Lifestyle Podcast: ✨ Apple Podcasts: https://apple.co/3ogQDBd ✨ Spotify: https://open.spotify.com/show/77XDkcNfzZCasJXL672h01 The Longevity and Lifestyle Podcast is dedicated to everyone who wants to increase their lifespan, improve their quality of life and unlock peak performance. Don't forget to follow so you never miss an episode!
In this episode of "The Human Upgrade with Dave Asprey," Dave welcomes Kashif Khan from the DNA Company. Kashif shares his journey in functional genomics and how he unintentionally reversed his biological age by 10 years. They discuss the importance of understanding your genome and its impact on aging. Kashif highlights the DNA Company's approach to genetics, focusing on identifying biological functions and finding personalized solutions. They explore the connection between genetics, habits, and aging, emphasizing the need for context-based choices. Kashif also reveals how his genetic profile influenced his gut health and neurochemical balance. Finally, they touch on the role of upbringing and lifestyle in overall health. Don't miss this insightful conversation on unlocking the secrets of functional genomics for a healthier, rejuvenated life.WE APPRECIATE OUR PARTNERS. CHECK THEM OUT! The DNA Company: https://www.thednacompany.com9th Annual Biohacking Conference: You'll learn from dozens of experts at an amazing event that's designed to upgrade every area of your life. https://biohackingconference.comIf you're coming to the conference, after Kashif's session he will be signing copies of his new book, “The DNA Way: Unlock the Secrets of Your Genes to Reverse Disease, Slow Aging, and Achieve Optimal Wellness.” See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Kashif Khan discusses Functional Genomics with Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on my WeitzChiro YouTube page.] Podcast Highlights 4:12 Genetics vs Functional Genomics. The difference between genetics and functional genomics is that genetics might tell us here's what this gene does and we'll speak about it independently. For example, when it comes to methylation, you might say that you have the MTHFR gene and you need to take folate is genetics. Functional genomics looks at how the body actually works and recognizes that methylation is one part of phase two of detoxification. There is also glutathionization, glucuronidation, and antioxidation. There's all these detox functions happening in the body. And if I don't pair them, I haven't understood the full cascade. What does my body do from the point that a toxin enters to the point that it gets out? So first understand that, and there's not one gene that does every single step along the way. There's multiple processes. When you connect them and you have your full functional answer, you can then solve the problem fully also. 5:39 Kashif made an appearance on Ari Whitten's Energy Blueprint and Ari asked if a woman has the BRCA gene should she have her breasts cut off? The genetic answer is yes, but that is because pure genetics is pharma and disease backwards. If you have the genetics and you ask why are you waiting to treat the disease, then you would remove the breasts. If you ask the wrong question, you get the wrong answer. But instead, if you ask why does the disease happen in the first place? You understand that BRCA doesn't cause cancer. BRCA is actually a tumor suppressor and when you have breast cancer, BRCA is supposed to come along and fix it. And if you have the wrong version, you just have a bad repair tool. So you're more likely to die from breast cancer because you can't come back from it. So we're solving the wrong problem once again. Why did the cancer happen to begin with? That question is better answered by looking at if the woman is estrogen dominant and does she make a lot of estrogen? Also, how does she metabolize her estrogen, which can be analyzed with DUTCH testing that measures which pathway the body uses to metabolize estrogen--the 2, the 4, or the 16 hydroxyestrogen pathway, with the 2 being healthiest and 4 and 16 being more toxic. Bad genes do not equal disease. You also have to look at diet, lifestyle, and environmental exposures. This woman's bad choices may be that she goes on the birth control pill for 10 years that elevates her estrogen level. Then she goes on Bioidentical Hormone Therapy (BHRT). Not that you shouldn't go on BHRT, but if you take the wrong form of estrogen and if you cook with a teflon pan and use conventional cleaning chemicals and get exposed to pesticides on her lawn that fuel the 4-hydroxy pathway. Why do we see breast cancer more commonly around the menopause age? It is because at that age, you no longer have a menstrual cycle and you no longer have the ability to get rid of this toxic load that you're making every month. And your body stores it in fat, such as in your breasts, to protect you because it doesn't want your organs and your vasculature getting damaged. This reduces potential inflammation in the arteries, but it leads to inflammation in the breasts and you may get cellular degradation, mutation, and eventually cancer. And if you have the wrong version of BRCA, you're not going to fight the cancer so well. Kashif Khan is the Chief Executive Officer and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. The website is TheDNAcompany.com.
Dr.Azra Bihorac is senior associate dean for research at the University of Florida College of Medicine and is the R. Glenn Davis Professor of Medicine, Surgery, Anesthesiology, and Physiology & Functional Genomics; the Lab Director of the Precision and Intelligent Systems in Medicine Research Partnership (PRISMAP); and Co-Director of the Intelligent Critical Care Center (IC3), a multi-disciplinary center focused on providing sustainable support and leadership for transformative medical AI research, education, and clinical applications to advance patients' health in critical and acute care medicine. The journey of Dr. Bihorac's medical career has spanned multiple continents, from her time as a medical student at the University of Sarajevo in Bosnia & Herzegovina to her role as a dean at the University of Florida in the United States. Through her research, she is addressing an unprecedented opportunity for world-leading ambient, immersive, and AI innovation to transform the diagnosis, monitoring, and treatment for critically and acutely ill patients. Dr. Bihorac's vision is to develop tools for intelligent human-centered health care that is tailored to a patient's “personal clinical profile” using digital data. She is a nationally and internationally recognized expert in medical AI, data science, informatics, and translational research, and earlier this year she was interviewed on NBC Nightly News and NPRabout the future of artificial intelligence in critical care. Dr. Bihorac is currently a PI for multiple NIH-funded programs, including a $23.5 million, multicenter Bridge2AI project called “A Patient-Focused CHoRUS for Equitable AI,” which seeks to develop a 100,000-patient dataset for AI research in critical care along with AI workforce training events and a set of standards for the ethical use of AI in critical care.
We are joined by Cee McDermott, a Precision Wellness Practitioner, who leads high achievers to wellness and enhanced cognition through epigenetic and lifestyle modifications. In this episode, we discuss the biggest variables for turning our genes off and on, specific genes for fat metabolism, the impact cold & heat therapy can have on our genes, psychedelics & genetic variants, tips for raising healthy children, the newest longevity research, the importance of mindset for overall health, and more!Cee McDermott is a Precision Wellness Practitioner based in New Jersey. Cee focuses on preventing disease and optimizing lifestyle through nutrition, behavior change, mindset, and stress management. Cee is a Cognitive Health Specialist, a Behavior Change Expert, a Certified Personal Trainer, a certified Genomics coach, Kundalini Yoga teacher, the founder of Cee McDermott Genomics, and the author of the International Bestselling book Your DNA, Your LIfe. Cee currently runs the operations of Apeiron Genomics LLC and is continually expanding her genomic and epigenetic knowledge through education and personal experience.SHOW NOTES:0:51 Welcome to the show!2:01 Pop Quiz of the Day3:20 About today's episode6:12 Cee McDermott's bio6:56 Welcome her to the podcast!7:37 What are the biggest variables for turning our genes off or on?9:30 How to optimize Sleep Chronotypes11:34 The CLOCK gene13:30 FTO & APOE-3/4 genes & fat16:15 How to get started with genetics?19:51 Cold & Heat Therapy23:21 Additional triggers of epigenetics24:42 Exposure to dental amalgams28:02 *Paleo Valley*30:25 What early-childhood variables are important?35:26 Psychedelics & Genetics38:32 Renee's story about THC40:35 Apeiron's genetic panels42:01 New Longevity research46:48 How will social isolation affect our children?49:25 Renee's story about kids in our family50:25 Advice on supporting our children with tech54:18 Renee's story about the Blue Zones56:45 Mindset advice in her book1:01:55 How we share microbiomes1:02:57 Her final piece of advice1:03:43 Where to find her1:04:14 Thanks for tuning inRESOURCES:Website: www.ceemcdermott.comIG: Cee_McDermottBook: Your DNA, Your LifeApeiron Genetic TestingPaleoValley - Save 15% with this link!Support this podcast at — https://redcircle.com/biohacker-babes-podcast/donationsAdvertising Inquiries: https://redcircle.com/brands
As part of the Peak Human Anti Aging Summit, Dr Sanjeev Goel speaks with one of the preeminent functional genomics experts in the world, Dr Mansoor Mohammed on aging and longevity.
You didn't get to choose your DNA, but you can do what's best for your unique makeup! Join us for this interview with Kashif Khan, the CEO and Founder of The DNA Company, where he shares the science behind genetics and the impact our lifestyle choices have on DNA. We discuss the biggest environmental factors, functional genomics & epigenetic expression, his thoughts on the genetic link to obesity, insight into our personal results, and what we need to know about methylation.Kashif Khan is Chief Executive Officer and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. With the largest study of its kind globally, The DNA Company has developed a functional approach to genomic interpretation overlaying environment, nutrition, and lifestyle on the genetic blueprint to create personalized and deterministic health outcomes.SHOW NOTES:0:51 Welcome to the show!1:09 Pop Quiz of the Day3:13 Today's interview topic5:24 DNA Privacy Protection6:39 About Kashif Khan8:21 Welcome, Kashif!9:19 Why should we test genetics?10:44 What are the biggest environmental factors?12:46 Renee's experience with Bulletproof coffee12:49 APOE-2 Gene14:15 The difference with Functional Genomics16:47 Lauren's experience with Bojangles19:02 What is Epigenetic expression?21:01 What is Functional Genomics?22:32 How do we know a gene will express?25:08 Is Obesity genetic?28:03 When to bring in supplements30:17 Personalizing women's hormones31:43 *Sleep Breakthrough*33:28 What about hormone testing?35:10 Our ApoE-3/4 Genes & Cholesterol37:05 Our similarities & differences as sisters47:56 How does behavior affect BDNF levels?49:05 Why Finnish people are the happiest!51:45 How to support motivation54:48 What do we need to know about Methylation?56:59 Nutrient Co-factors & delivery formats1:03:23 His final piece of advice1:05:09 Where to find more information1:06:38 Thanks for tuning in!RESOURCES:Website: The DNA Company - discount code: BIOHACKERBABESInstagramLinkedInSleep Breakthrough - discount code: BIOHACKERBABESBiohacker Babes 7-Day ChallengeSupport this podcast at — https://redcircle.com/biohacker-babes-podcast/donationsAdvertising Inquiries: https://redcircle.com/brands
What is the obesity gene? What are the longevity genes? Do you have the genes that make you a poor candidate for the keto diet? What makes some people more prone to PTSD and stress? What are the pros and cons of ADHD? What are the different addictive behaviors and how do our genes determine if we are a daily risk/reward seeker or a binger? How do these addictions translate into mental health and career tendencies? Harris Khan's mastery of the knowledge of functional genomics makes this episode a fascinating listen. Starting from the pharmaceutical industry in testing for billion-dollar drugs to developing genomic metrics to help people understand their own unique requirements for diet, exercise, mood/behavior, sleep, hormonal health, cardiovascular predilections, and anti-inflammatory and detox capabilities. This will revolutionize how we treat each individual, and give physicians powerful tools to provide tailored treatments for each unique individual. Become informed on who you are and why you are the way you are with functional genomics testing.Get your functional genomics testing provided by The DNA Company and receive $50 off through this link: http://thednacompany.com/uplyftTo Connect with Harris Khan:https://www.thednacompany.com/To Connect With Dr. Joy Kong:http://drjoykong.com/Watch Video Episodes on YouTube:https://www.youtube.com/channel/UCZj1GQBWFM5sRAL0iQfcMAQFollow Dr. Joy Kong on Social Media:https://www.instagram.com/dr_joy_kong/https://www.facebook.com/stemcelldrjoyhttps://www.linkedin.com/in/joy-kong-md-4b8627123/For more information about anti-aging regenerative medicine treatment visit:https://uplyftcenter.com *Our content is for informational purposes only and should not be treated as medical or health advice. Please consult with your doctor / healthcare provider if you have any questions about your medical conditions.*
In this episode Alex talks with Caroline Sabbah. Caroline is a functional nutritionist and a functional medicine practitioner. She works as what she defines as a functional Womenologist with a focus on functional Womenology combining Functional Genomics (genetics/DNA) and Coaching for Women's Health and Well-Being from the inside out. Episode Highlights: - Difference between genetics, genomics & epigenetics - Why genetic testing is important - What our genes can reveal about ourselves - What can impact our genes - How our genes can impact our hormones, weight, performance, mental health, etc. - & so much more! Connect with Caroline: - Instagram: @carolinemsabbah - Website: carolinemsabbah.com - Free Guide to Genetic Testing Connect with Alex: - Currently accepting new clients worldwide! Work with me here - Coming Off Birth Control ebook - Free resources - Instagram: @nutritionmoderation - TikTok: @nutritionmoderation - Website: www.nutritionmoderation.com DISCOUNTS: - Get 10% off the TempDrop thermometer with code AFNUTRITIONMODERATION - Use code ALEXKING to get 10% off your Twistie cup at twistieonthego.com - Get 10% off at Greenhouse Juice using code NUTRITIONMODERATION - Get 15% off at Giddy Yo using code ALEXANDRAKING - Order the Mira Starter Kit or the Mira Plus Bundle online at miracare.com using the promo code ALEXKING to get 10% off
Do you ever wonder why you can't seem to find the motivation or energy to do what it takes to stay fit and healthy? Do you ever feel like something is wrong with your genes and hormones? Our guest Kashif Khan is an expert in functional genomics and has been helping midlife women understand the science behind their hormones and genes. He shares with us how understanding the function of your genes can help you engineer your hormonal system, leading to better health, more energy and improved fitness! About Kashif Khan: Kashif Khan is Chief Executive Officer and Founder of The DNA Company, where personalized medicine is being pioneered through unique insights into the human genome. He is also the host of the Unpilled podcast. Growing up in Vancouver, Canada in an immigrant household, Kashif developed an industrious entrepreneurial spirit from a young age. Prior to his tenure at the DNA Company, Kashif advised a number of high-growth start-ups in a variety of industries. As Kashif dove into the field of functional genomics as the CEO of The DNA Company, it was revealed that his neural wiring was actually genetically designed to be entrepreneurial. However, his genes also revealed a particular sensitivity to pollutants. Now seeing his health from a new lens Kashif dove further and started to see the genetic pathways that led to his own families challenges, and the opportunities to reverse chronic disease. His measure of success is not in dollars earned, but in lives improved. In this episode, you'll learn: • How understanding your genes can help you engineer your hormones • What functional genomics is and how it can benefit you • How to use genetics to optimize health and fitness • Ways to reverse chronic diseases through genetic insights • Tips for finding the motivation and energy to stay fit and healthy. Don't miss out on this powerful episode with our guest Kashif Khan, Chief Executive Officer of The DNA Company and host of the Unpilled podcast. Tune in to discover how understanding your genes can help you engineer your hormones and stay fit and healthy! (00:00): Healthcare is studying the habits of those with the genes who didn't get the disease. And teaching that to the people who don't know. (00:11): So the big question is, how do women over 40 like us, keep weight off, have great energy, balance our hormones and our moods, feel sexy and confident, and master midlife? If you're like most of us, you are not getting the answers you need and remain confused and pretty hopeless to ever feel like yourself again. As an O B gyn, I had to discover for myself the truth about what creates a rock solid metabolism, lasting weight loss, and supercharged energy after 40, in order to lose a hundred pounds and fix my fatigue. Now I'm on a mission. This podcast is designed to share the natural tools you need for impactful results and to give you clarity on the answers to your midlife metabolism challenges. Join me for tangible, natural strategies to crush the hormone imbalances you are facing and help you get unstuck from the sidelines of life. My name is Dr. Kyrin Dunston. Welcome to the Hormone Prescription Podcast. (01:05): Hi everybody. Welcome back to another episode of the Hormone Prescription with Dr. Kyrin. Thank you so much for joining me today. My guest today is gonna shed some light on why genetics are so important when it comes to women's health, particularly over 40. We haven't focused in this way on genetics and epigenetics in the podcast. So I thought it's super important to have KIF on the podcast to really shed some light. And I wanted to start with that quote because you know, we take for granted that what we have is healthcare in America and most developed countries, and we call it that healthcare, but really it's just disease management. It's actually not the creation of health. So I love when K, she K, she says this, healthcare is studying the habits of those with the genes who didn't get the disease. And teaching that to the people who don't know. (02:01): We used to think that there was genetic determinism after DNA sequencing was discovered several decades ago, and the Nobel Prize was awarded to Watson and Crick. And then we had this genetic determinism where all diseases determined by genes, it's predestined. It's out of our control. We don't have to worry about it. And in fact, when I practiced regular ob gyn, I would've women all the time come to me and say, oh, my mother had a hysterectomy at 45. It's time for mine as if that were genetically predetermined. It's not. In fact, genes only dictate about 10, maybe at most 20% of your health. But it's what genes get turned on that matters and what genes get turned off. And this is something called epigenetics epi, meaning above your genes. It turns them on and turns them off. So what creates health is your life habits that either turn certain genes on that you want or turn genes on that you don't want or turn bad genes off or turn good genes off. (03:08): So it's all about epigenetics. So we're gonna dive into that in great detail. He's gonna dive into the topic of breast cancer, how it's not estrogen that causes breast cancer. Hopefully you don't believe that because all men and all women on the face of the planet have estrogen. And so if estrogen caused breast cancer, 100% of all men and all women would have it. And we don't. So it's something else. And one of the things that it is, is what your body does with that estrogen. So we're gonna dive into that and that's genetically determined. And you do have the power, you have the control to turn those genes on or turn 'em off. So which will you choose? I will tell you a little bit about Kashif and then we will get started. So Kashif is the chief executive officer and founder of the DNA company. (03:58): We're personalized Medicine is being pioneered through unique insights into the human genome. He is also the host of the Unfilled podcast. I love that name. He grew up in Vancouver, Canada in an immigrant household. And he has an industrious entrepreneurial spirit that he's had since he was a little kid before he started the DNA company. He advised a number of high growth startups in a variety of industries, but he's really, he dove into the field of functional genomics as the CEO of the DNA company. And I really love his unique perspective on this. Sometimes we insiders can't see things the way that outsiders do and he actually not only sees it, but can articulate their certain concepts importance in a way that I think is very impactful and unique. So please welcome Kashif to the podcast. Welcome Kashif to the Hormone Prescription Podcast. (05:00): Pleasure, honor to be with you. (05:02): So excited to have you. I love talking about DNA and epigenetics and what people can do to turn certain genes on or off. And I don't think this really is a part of mainstream medicine yet. So women wanna hear about this. They wanna know what's out there and available for me to really make my health the best it can be at midlife and beyond. But first I gotta ask, how did you become so passionate about working with human genetics? (05:33): Well, we, we were a research company, but bringing it to the public, actually it was a female hormone issue that got me there and it was actually with my niece. So I've had my kids, three kids and my niece genetically tested who are all close to me to understand, you know, personalized diet, fitness, even academically, how is their brain wired hormonally, how is their body developing? What sports should they play? So I've learned a lot about how to personalize the parenting for them. And what happened is my niece actually had a anxiety crisis where she just collapsed and she actually hurt herself. I had to take her to the hospital. And I realized they're just like any concern parent uncle, like I was just reacting to the problem. Oh, she has anxiety. Oh, she has pain. And I was borderline almost about to accept that pill prescription. (06:21): And then I realized, hold on, what am I doing? I have her dna, I have a deeper understanding of her biology. And so I realized that the three times that it happened was they were about a month apart. So I asked my sister or her mom, does this have anything? Like what's the timing of the menstrual cycle? And she said, you know what? You're right. It was right before it started. Every time, right before the menstrual cycle started, this is when she had these anxiety attack and crashes where she literally fell over, couldn't breathe. So I looked at her genetics and we've mapped out the hormone cascade to a T where we understand how you produce certain hormones. To what degree, how well do you clear them? How toxic, how they are clean, are they, she was void of estrogen. She was highly androgen dominant, didn't produce enough estrogen. (07:05): And we know that at the beginning of that hormone cycle is when you have the least estrogens, right? Then you start to make them. And if you have less to begin with, then that delta value for is even lower. Like she has this very deep belly she goes into with no hormones, no hormones, right? And so that was one thing that, why did it happen then? Well, this was two years ago in the Toronto winter during covid lockdown. And she hadn't been outside in like four months, right? This was like 2020 winter. Pure lockdown never left. So she got zero vitamin D of the 30,000 genes that make up your body, 10% of them require vitamin D to function. It's actually another hormone if you really look at it correctly. Right? And so she already had this hormone issue, which we could look at genetically. (07:56): She wasn't getting enough vitamin D, which triggered a 10% biochemistry, chaos. And then when you look at the genetics of her brain, she doesn't bind dopamine properly. So it's very easy for her to experience depression, anxiety, negative stimulus. Mm-hmm. and this cocktail of all these problems, plus not having gone outside for four months equaled anxiety crash. She would have been on an anxiety pill if I didn't know all this. But all we did was I gave her altheine to booster dopamine levels and I gave her 10,000 IU vitamin D in the very first week of her cycle, then 5,020 500. And we did that every month. It's been two years. She has not had this problem. Right. So when I went through that very long answer to your question mm-hmm. is that, that's the thing that made me go from, we are not a research company. Every woman needs this. Every woman, how many young women like her are struggling with anxiety issues? How many women are struggling, infertility issues, crazy menopause, all this stuff that's treated so gray, which is actually black and white if you understand it genetically. (09:03): Yeah, I love that story. It's very illustrative of the power of knowing your genetics. But yes, she would've ended up in a mainstream doctor's office on an anti-anxiety medication and probably a birth control pill. Usually any symptoms that are cyclic, we gynecologists wanna put every woman on a birth control pill, which basically just shuts the whole female hormone system down. But what most women don't realize is the, the complications they're gonna have from the hormonal balances that it cause causes. So it's not the way I go now as a functional doc . All right. So that certainly got you passionate about it. I love that story. And then what has, I mean, you're obviously an entrepreneur at heart. You, you've worked with startups in variety of industries, but it sounds like you had a personal story that really grabbed you here. And what are some other stories that you might share of how you've seen this impact women's health? (10:07): Well, so first of all, you're right on what they said is anxiety pill plus birth control. (10:13): Yeah. (10:13): That was the prescription, right? And I said, no way. We're not doing that. And that's what triggered me to dive into our genome. So I can't tell you how many women, so let's look at breast cancer for example. When you think about genetics, that's probably the biggest area where women think about the genes as you know, brca the BRCA gene. And that's scary. Four letter word. And if you ask a woman, do you want bracker? No, no, no. I don't. I don't want brca. If you ask a doctor, what do you think about? Oh, scary, scary, scary. But if you ask them what does it do? They don't know, right? , they don't even know what it means. You, you need brca. BRCA is a tumor suppressing gene. If you have, god forbid, cancer, it goes and fights it for you. That's what it does. The challenge is if you have the bad version of a variant end, it doesn't do a good job of repair. (11:00): So either or, even if you have the worst version, it doesn't cause cancer. What it does is, does you lack the ability to fight. So we still need to ask the question, why did you get breast cancer in the first place, which is a female hormone issue that we don't understand or look at. Uh, in fact, you go to most cancer research websites and all these and they, they tell you, we actually don't know why. We're more more focused on how to treat it. So let's look at that example. Bad brer, why did you get it to begin with? This is one of many examples. So some women are, unlike my niece, the opposite. They're more estrogen dominant. So this is step one of three in that hormone cascade. You go from progesterone to testosterone to estrogen. That's what you do. There's some nuances in there. (11:43): Other things you can do. But that's the general lame, right? Some women just convert into a heavy bucket of estrogen. That's what they do. Step two of three, you then need to create a metabolite, either two, four or 16. Hydroxy, estrogen. That's what you make it into. Two is great, nice clean stuff, four and 16, highly toxic, you don't want them, right? Then step three of three, now that you know you may be estrogen dominant and estrogen toxic, what are the detox systems that are supposed to kick in and clear that stuff and help me get rid of it, which is glutathione and ox antioxidation. Those are the two key areas. Step four, there's another step four we can look at, which is methylation, which is your antiinflammatory response. If you're not doing those things well. So if that's you estrogen dominant, estrogen toxic, I don't detoxify, you now get put in this bucket of high risk. (12:35): But still not every woman gets sick. What happens? 85% of North American women, I can speak to North American data cuz that's where I am. Mm-hmm , 85% of North American women will be on a birth control pill for 10 years, right? For fielding that estrogen fire. Every woman as she reaches sort of midlife is told to get on hormone replacement therapy. Now without understanding which one and why, which is what you're so good at, right? And just, yeah, take it. Just go ahead. You're supposed to do it fueling that estrogen fire. Women have no clue for the most part, maybe not your audience, but for the most part the hormone des disruptors that they're dealing with every day, the cord and frying pan, the chemicals, the pesticides and the lawn. Everything that they're breathing and eating and coming through their skin that their body just treats as more hormones and fuels. (13:24): That toxic fire. That's the woman for whom you have the genetic profile. And you've also made the wrong epigenetic choices unknowingly that now you feel that fire so much that it causes inflammation. So why then is menopause the time when this happens? Why is that where you find most breast cancer? Cause now all of a sudden you don't have a menstrual cycle to get rid of that monthly dose of estrogen toxicity. And your body wants to protect you. It doesn't want it free flowing in the blood, causing inflammation to your organs and your, your endothelium, your vasculature, your veins. So it goes and stores it in fat. And where do you have fat in your breasts and what's in your breasts that was never designed to deal with that level of toxic insult is all these glands to deliver milk that get inflamed, get damaged, become cancerous. (14:13): And that's the point when BRCA is supposed to start working right now, all of a sudden the tumor supporting gene is supposed to come in and fix the damage you did. Mm-hmm. . But even then, why have cancer to begin with? If you understand this is what's happening with your hormones. If you understand these are the choices you need to make and you understand that there's a right and wrong way to do hormones for you as an individual, right? You shouldn't have ever had it in the first place. And this is all we're saying is that if you are ill, we can help or anybody can help by using functional genomics. Why? As opposed to what, then go ahead and treat, treat it. You need to do that. But let's find out also why if you're not yet Ill, let's make sure it never happens. Let's prevent all this nonsense from ever happening. Cuz you, you can be armed with the right choices. (15:00): Boy, you brought up so many great points in there cuz sheep, let's just go back cuz that was so powerful. I hope everybody listening really heard what he's saying. So number one, you said they're only concerned with how to treat breast cancer, not why you get it. And I hope everyone heard that because it's true the pharmaceutical industry and most researchers are not overly concerned with why you got breast cancer cuz they're not interested in preventing it. They're interested in treating it because unfortunately in our capitalist society, that's where the profit is. And also you mentioned the detox pathways, the 2 4 16 hydroxy, um, estrogens. And what most women don't realize is that their regular doctor is not gonna ever check those on them. But if you heard, because she said he was saying that this is vital to know as part of why did you get breast cancer. Cuz if you're detoxifying your estrogen down negative pathways, you're more prone to making toxic metabolites that will go on to create cancer. And that includes the 24 16 issue. There are enzymes involved with that, but also the, the glutathione and the methylation. And there were so many other things important in there that you said how women are afraid of brca and I can't even remember, I took some notes on what you said to, to comment on it. Anything else you wanna add to that? Cause I think it's super important what you said. (16:32): No, I think you're right on that the toolkit, right? When you go to the doctor, doctor doesn't have bad intentions, right? They're just limited by the tools provided to them and what they're trained on. And what they're trained on is how to treat. So even if you get into their, if you ask an oncologist or doctor that you don't tell me why, they'll say, yeah, we do. We look, is it her, her two positive? And like what kind of a But all of those things only ever lead to which treatment do you need, (17:00): Right? (17:01): Right. The the, the only why you'll get is what directs a drug or a treatment, not here's why you don't need to be in the hospital. That's really the answer you want. Right? Healthcare should be, how do I stay healthy , how do I get rid of this illness? I was born healthy. Yeah. I wasn't born with breast cancer. Why did it happen? Now why does most chronic disease happen to somebody? Well, the North American average, by the way this is the American dream, is by the time you're 55 you have a chronic disease. That's the average. By the time you're 65, you have two and you spend the last 15 years of your life in treatment. That's the expectation of things that you're not born with and you don't innately have. Right? And it's so much worse for women because of the cofactor of estrogen dominance and, sorry, I should say more precisely estrogen toxicity. 66% of women will die on their first cardiovascular event with zero symptoms, zero previous warning signs. They don't even know that their cardiovascularly ill, they'll have some kind of heart attack, blockage, whatever, and they will die because there's so much more inflamed than the men. The men. It's a tiny fraction. So women have to pay so much more attention, not only to the hormone issues themselves, but all the other chronic diseases for which you're fueling a much more aggressive version of it. (18:27): Right? That is a, a powerful point. And you're so right. And we take for granted what healthcare is because we're socialized into it from the time we're born. But if doctors really were concerned with the prevention of disease, they would be talking to you about diet, lifestyle, sleep, all these things. And it's not what we do. We've got a prescription pad. We do drugs and surgery. Drugs and surgery. And that's what we do. So the average woman is not having a BRCA test. She's not having her phase one and phase two liver enzyme detox pathways. Yeah. Uh, genetics mod profile. Done. What do you think are the most important tests for women to have when it comes to functional genomics? (19:14): So this is self-serving, but we've built it, right? And why? The reason why we built it is cuz just like when my niece went through it, genetic tests don't serve hormones properly because you can't look at, so first of all, what does genetics? This gene means this, this gene means this, this gene means this. That's genetics, right? You got a report that tells you what version of what gene you have. And now somebody that has some knowledge will go interpret that somehow. But that's not the way the body works, especially when it comes to hormones. There's a, there's a cascade. It's not this gene does this. One step won't direct you. You need to know the full system flow. I make progesterone converted into testosterone. How quickly, how much testosterone do I make? Do I then convert that into dht? Do I clear it? Do I convert it into estrogen? (20:00): And then what version of estrogen do I then make? So if you haven't mapped all of that out, you can't really make a call. And this is why genetics 1 0 1, which is what most genetic researchers do, hasn't really addressed hormones. Functional genomics, just like medicine is, what disease do you have? Let me give you a pill. Mm-hmm. , that's what genetics is. Also functional medicine is let's figure out why you got sick to begin with and change your habits. Mm-hmm. , that's what functional genomics is. Let's map the pathway in the context of the body actually works. And then we know exactly where to intervene. We can predict, we can then predict how you do all of these jobs in your body. What is, what is dna? DNA is an instruction telling yourselves what to do. If you know what version of what gene you have, you know, one job. But if you don't understand the entire assembly line and what, what everybody else is doing, can you really make a call? Functional genomics is, let's look at the full system, the pathway in the context of human biology. Like here's what the body actually does. Now let's reverse engineer the genes that instruct each step, that baton pass along the way of that process, right? So now you can take this very gray area of female hormones, which you ask any woman what her experience is medically. And it sucks, right? , it's just like (21:17): Universal. (21:18): Yeah, universal. Like the answer is you're supposed to have problems. It's your hormones, right? Like it's a, you're a woman, you're supposed to have problems. That's the belief. (21:29): That is the belief. (21:30): And why? Because it has been mapped the way that I just described earlier. This gene means this, this, she means this, this hormone means this, this pathway means this. The entire cascade has been looked at openly as this map. Where would you then read then you can determine exactly what's going. And you make this, like I said earlier, this very gray thing, very black and white, very certain. It is that certain. And now you know exactly what risks, what problems, how to prevent and how to have a wonderful menopause, how to have wonderful fertility, how to have a great menstrual cycle, right? It can be that way. And it is now more challenging and more problematic than ever because the load of hormone disruptors and chemicals we're dealing with is more than ever before. And this is also partly why the sort of medical practice has in advance because grandma's generation didn't have the problems that this generation has because they weren't exposed to this level of chemicals and horrible food and lack of sleep and all the other things that are co-factor to these hormone problems. So it's even more important ever than than ever before today to look at it deeply. (22:38): Yes. So I know a lot of people get very excited about tests like 23 and me, I had it done a while back when it first came out and really wasn't impressed with the action actionable information in there. I mean, I don't really need to know that I have the gene that I can smell the asparagus in my urine after I eat it. , (23:02): You probably know already. (23:04): I knew that already. I don't find that very useful. And it seems like most of these tests that, that are available online, or let me just say a lot of 'em are not actionable information. How can the average woman discern among genetic tests? What's worth my time, energy, and money that's actually going to give me actionable information that's going to impact my health? How does she know that (23:33): It has to be a functional genomics test, right? What does that mean? Genetics is what does this gene mean? And unless a gene has one singular purpose, you can't really say anything about it. Functional genomics is of the 30,000 genes in your body, there's only a hundred that matter for most chronic conditions, hormones, brain detox, diet, nutrition, and a few other things, right? So what we've done is we've created a hormone panel and in that all that, you know, so the genetics of this gene does this and your, your piece smells because of asparagus. Great. How do I make hormones? How do you map that? How do you make it actionable? The reason why we're able to do that is the research itself. So most genetic companies, there's a researcher, our lab who receives your sample in the mail who then puts it through an algorithm and you get a report. (24:25): And that researcher is studying the DNA in a Petri dish somewhere, right? We said that's exactly the problem. They never met any of their patients and talked to them. They don't actually meet them and say, how do you feel? How did this supplement work? What happened you when you ate this food? So that's what we did. We spent three years, uh, studying 7,000 people in, the majority of them are women. So we actually partnered with a number of clinics that dealt with breast cancer and infertility and hormone issues and all these different things. And we said, we'll work on the testing in our research and we actually wanna meet these women. And we sat down with them for hours, sometimes months, depending what the problem to document what, how are they eating, how are they exercising, what were the, what was their chemical exposure? And now those things are in the report and actionable. (25:11): So when you log in, it's called the DNA 360. So when you log into the DNA 360 portal, yes you're finding out about your dna, but you're also being told, here's for this problem, anxiety keto diet, separated by the problem for anxiety. Here's your rank and here's the supplements that you need to take. Not that everybody needs to take take, but that you need to take. Here's the food that you need to eat, here's the habits you need to adopt. We hired Dr. BJ Fog, he runs the Stanford University Behavior Change lab. So he's a guru when it comes to behavior change. He wrote the book Tiny Habits book, right? We hired him. Yeah, it's amazing. So it's like how do you actually change your identity? So we spent a year with him taking all of what I described and then he put the behavior change insights into it. (25:58): So it's easy. So it's like here's how you actually, here's what's wrong, here's how you fix it and here's how you actually implement it. The easiest way to implement it. So all of a sudden that's what action is, right? Action is not tell me what's wrong and then say good luck . It's telling me what's wrong. Yeah. Like you got an 80% chance of Alzheimer's, see you later. Right? That's genetics, right? No, it's, you got an 80% chance of Alzheimer's. But by the way, the 20% that didn't get it with your genomic profile, here's what they did, right? Mm-hmm. , that's healthcare. Healthcare is studying the healthy and teaching those habits of the people that don't yet know, right? That's maintaining health, uh, masking illness. So that's what we did. We studied the healthy, we learned all those right things, things we can now teach them to the people that have the 80% risk of whatever and how do you implement it? Here's the behaviors you need to adopt to make it easy. So that's all built into the report. Cause if it isn't easy, it isn't actionable. Right? Part of it being actionable is it has to be easy to understand and use. You shouldn't need a PhD to decipher it for you who then may have an opinion on what they actually think it means. Right? (27:07): Right. Yeah. That's super important. I love what you said. I wanna reiterate that you basically said healthcare is studying the habits of those with the genes who didn't get the disease and teaching that to the people who don't know. And I, I think for everyone listening, you need to realize that you're at risk for some diseases and you have no idea about what you're at risk for because you haven't done a genetic profile that's actionable that tells you what you're at risk for. So you're just blindly going down the road. And then one day you might get a diagnosis of Alzheimer's or dementia or cancer or something and then people say, oh, it came out of the blue. And what I say is, it didn't come out of the blue, it came out of the oblivious because you didn't know. Because it's not the standard of care for physicians to be checking their patients, most of them, their genetics. (28:11): And just imagine the power that you can have that you can get if you take action now, get this information and see, oh, I'm at risk for A, B and C. Let me learn what the people who were also at risk for a, b and C did who didn't get that disease. And then you can start doing it 5, 10, 20, however many years prior and maybe avoid that problem. And I know there's some people who are gonna reach out to me and say, Dr. Kyrin, well why, why doesn't my doctor do this? Why doesn't my HMO pay for this? Why all these things? And but a lot of you have heard me talking about this for so long. You know the answer. Right? And that's, we've talked about it today. That's not what healthcare is about. It's not what medicine is about. (29:02): Yeah. And that's, that's part of, I mean, trap is the best word to call it. Part of the trap is, oh, it's not covered by my insurance. I don't, you've been, you've been taught in that there's an entitlement around healthcare, right? That whatever's covered is good for me and what's covered is not acceptable. So that's the challenge. 60% of American personal bankruptcies are from healthcare costs. Literally. Can you imagine two thirds of per us personal bankruptcies are from people that's worked their entire lives to give it all up to st try and stay alive. And then even that doesn't work. They have to go bankrupt cuz of how expensive it is to treat illness. So isn't it a lot more effective to instead of saying, oh, this few hundred dollars is not covered by my insurance, instead to know exactly how to not have to spend half a million dollars on treating cancer when you're 60. Right? And, and the, and the challenge with health is because of the way we've been taught, it's our belief is I can do whatever I want and when I break something, it's a doctor's job to fix me. Right? That's the challenge. And we believe that. (30:13): We believe that. (30:15): Then guess what? Then you're on the path to breaking something and going to the doctor to fix you. You've already made that choice. Or health can be, I'm gonna learn everything I could possibly do to never get sick. Right? And when you look at the people that are, that are uber wealthy, that are selling you all this stuff, they're not in a hospital at the last 15 years of their life. The queen didn't die in a hospital bed a month ago. Right? She was walking and being the queen. Right. . Why? Because she had all the right people around her maintaining her health, not masking illness. That's the ultimate luxury. But you're, I mean that, but we're not sold that. So you have to take control and do it yourself. (30:59): Yeah, it's so true. And it was when you were saying that statistic about cancer and the cost to treat it at this point, one in two of us will get cancer. And if you're in a partnered or married relationship, that means one of you is gonna get it and it's gonna be a bill of about a quarter of a million dollars. And the yes, the statistics on bankruptcy and healthcare costs is, it's staggering. So let's get onto too . I know, I think we made our point, but um, it can't be stated enough because despite, as much as I've talked about it for years, I still have people reaching out to me and complaining and saying, well my insurance should pay for this. And on and on and on. I think, you know, in a utopian society we would learn these things starting when we were growing up in grade school, we would learn how our body functions. We would learn how to eat, we would learn about the importance. But that's for another day. All right, so you've gotta have functional genomics in these last few minutes. I definitely wanna give people actionable information. We certainly will have links to the DNA company, which is your company in the show note. So people can go there and I think you've got a free download for them, right? (32:16): Yeah. And I'll make sure to set up, uh, a promo code. I want to honor everybody for listening and you know, taking the time to learn how to be better. So we'll set up, I'll just keep it simple, you know, Kyrin Dunston, I'll make it like KD 50, you get $50 off the test. So I'll make sure that's set up. Awesome. And then that, yeah, (32:34): And we'll put that in the show notes too. We'll have the link and the code. So don't, if you're driving, don't try to write it down (32:40): . So you know, this field of new genomic testing companies is expanding very rapidly. So there are a lot of options out there. And I have to say that one of the reasons why I wanted to have you on the podcast is this differentiation of the actionable genomic information that people are gonna get. The functional information, just like you're describing, you really map out the, the whole hormonal cascade for women. And I will say that all genetic tests are not created equal there to the 23 of the knees that I think are pure novelty. And then there are some other companies that provide services, but I, I haven't found the information is so overwhelming cuz it's so much and it's like, oh, you know, do these 15 things because of these, these genetics. But what kind of actionable information can women expect to get from a report from the DNA company? (33:42): We, when we studied those 7,000 people, we learned that there were six key areas. If, if we focus on those resolve most issues give you optimal performance and slow down aging. Right? So those are the six that we focus on. And if any anyone needs anything more beyond that, we recommend they speak to one of either their own clinician or one of our clinicians to dive deeper. If it actually is breast cancer or prostate health, we, a clinician should work on that. But the six areas are cardiovascular health. So everything around maintaining, cause that's, it's the number one killer and it's so easy to prevent. So diabetes, cholesterolemia, you know, hypertension, all that stuff. Then mood, behavior, everything about the brain. How do you think, how do you perceive, why do you not get along with that person? Why are you wired to be an accountant? (34:31): You know everything about the way your brain works, truly personality mapping to a T so that you understand why you thrive in certain things and there's friction on certain things. Why do you have anxiety, depression, addiction, tendencies, which you don't need to have, right? The third one is hormones, which speaks to hormone dominance and toxicity, the thing we're talking about. But it also speaks to things like cell cellulite, hair, skin, uh, fat retention. Why do you hit plateaus of not being able to lose weight When for women, when do you work out, you know, what time of the month, when do you lift weights, when do you do yoga? Cause it, it makes a difference depending what's happening in your hormone cycle, right? To get the best result and not get injuries. Then we look at innate cellular health. So immunity and detox. What is your body doing to prevent inflammation, which is a root cause of disease in general. (35:24): Mm-hmm , detox patient, you know, anti-inflammation, antioxidation, all that stuff. How healthy are the cells? We look at diet, nutrition. So at a macro level, should you be on avego vegan diet? Should you be keto? Should you be, you know, paleo? Like what is right for you based on how you metabolize starches and fats and your insulin responses. And then the micronutrients like vitamin D and C and zinc and all the other things that help you healthy. And the last one is sleep. So the genetics of, I can't fall asleep, I can't stay asleep, I sleep through the night, but I wake up feeling like I didn't get any rest. Those are three very different things. Genetic genetically, we understand why they happen and that's probably the fastest thing that gets fixed because it's almost instantaneously if you start doing the right thing, you start sleeping better right away and that supports everything else. (36:13): So sleep is when you detox, it's when your brain and your glymphatic system detoxifies. It's when you make your hormone, it's when you make your mental hor uh, neurochemicals. Like, so if you're sleeping well, you're already solving a lot of problems, right? So, and then that's why we focus on that as an outlying thing. So those are the six areas we focus on. And if you do these six things right, you're superhuman. Yeah. You just, you just extended your life by 15 years just by doing these things because this is where disease comes from. And if you don't have chronic disease, then you should live healthy with energy and vitality. (36:47): Yeah, and I love that you shared uh, mark Hyman, mark hs quote with me before we started. Your genes load, the gun, your environment, nutrition and lifestyle hold the trigger. It's so true. But I think that most people just aren't aware that what is the gun loaded with? That's what could I be facing? And I think it's so important to have information like a functional genomic profile that can help you make informed choices about nutrition and lifestyle. I know there are women all over looking for what, what diet should I eat? And we choose with our minds, but the truth is a lot of times our genetics have something to say about that, right? (37:30): Yeah, for sure. You're first of all the way you're even perceiving and the choice that you just made mm-hmm , five different people make five different choices cuz they're seeing the situation differently. Your ability to deal with trauma and pain and either use it or a tool or ignore it, is determined by one or two genes really. Some people literally imprint and binding trauma and they hold onto the feeling. Some people can't, they ignore it. You know, your ability to see details and be be able to prioritize all the stimulus around you, whether it's sound or noise or information that's all linked in serotonin. And so you, you even step one even understanding how you see the world, you know? And when, when we're coaching people clinically we, we usually start there. It's let's understand your brain because once we do that, we know how to help you comply and actually do the things you're supposed to do. (38:21): We know how to speak to you. Like if I come with all the bad news, are you never gonna talk to me again? Right? Are you or are you like myself who's highly reward seeking because I can't bind dopamine, so it's very hard for me to experience pleasure and reward. So I'm overly yeah, I'm I'm overly uh, I'll do it too much and I'll burn out. Right? So we start and then, and then if you also know that about yourself, you start to understand that's why in this scenario this doesn't work. That's why I behave like this. So anyways, just about getting into choices, it starts with even understanding how you perceive. (38:57): Got it. Yes. You're so right. And our perception is partly determined by our genetics. I think the point is well taken and I'm wondering if you can, you shared with me a quote from Seth Godin, the cost of being wrong is less than the cost of doing nothing. So as it pertains to the topic, we're discussing women at midlife, hormonal health and balance what I call hormonal poverty. What, how does this apply? (39:25): Very simple. Most of us don't do anything about prevention cuz we don't think we can. Now that you know you can and if you still don't, something is coming. We just don't know what yet. The reality is that when we think of our ancestors, we think of grandma and grandpa, your DNA is 200,000 years old. So we are like people of 200,000 years ago. What does that mean? That the reality that we now live in of a highly industrialized chemical society is what, 70, 80, maybe a hundred years old versus 200,000 years of what we are designed for. So the short answer is you're gonna be sick, we just don't know with what yet. So the risk of just doing nothing means you've consciously made a decision to accept that you're gonna be sick with something. The risk of doing something is that maybe you just did the wrong thing and you didn't need to trial an error and figure out what's right. (40:27): So start, start today. The earlier you start, I believe the sort of trifecta, and you hinted to this earlier, is you start with your genetic code because now you know what you're wired for, what choices to make. Then you go into epigenetics, which is environment, nutrition, light. Let's start bringing in the right habits. Then you get into tracking, which is let's, let's do blood work and let's do Dutch testing and let's figure out where is it not working out. This choice that I thought was right for me isn't actually moving the needle. So I need to know how to change it. So that's what you should do for healthcare. Initial mapping, genetic testing, here's who I am and here's my risk. Start to implement habits, here's the right choices for me and now I'm making changes slowly. You don't have to do everything at once as you can handle it. Start to make changes and then measure things. Work with somebody like yourself and keep measuring, work with Dr. Dunston and say, I wanna do this test, I wanna do this test. And then you'll start to see, oh, I move the needle. See reactive protein, way better. My inflammation is gone. But guess what? Estrogen toxicity is still there. Let me work on that. That's healthcare. That's you taking charge and making that conscious choice. Conscious choice and preventing, (41:42): Yes. So important. K Chief, thank you so much for sharing all this wonderful information. I love your passion for this topic. It, it really shows and I think that everybody listening really has a good idea for how impactful a functional genomic test can be. I hope you will all check it out. We'll have all the information in the show notes with all the links so you can go get a test. It's a place to start. Just start. Take action. , I would be remiss if I didn't ask you about the unfilled podcast. So tell everyone about your podcast and where they can connect with you on social media and on the internet. (42:26): So unfilled was really built for our customers just to learn. So we got so many questions that we get regularly. We thought if we just give that answer to everybody as opposed to one individual. So the Unfill podcast, rev, you listen Apple, Spotify, just look up the Unfill podcast, you'll find us. And it's essentially us speaking to healthcare issues from the genetic perspective. That was season one, season two just launched, which is us interviewing a whole bunch of healthcare experts about various topics and they were awesome interviews. The the most recent one that just went live is with JJ Virgin about nutrition. And then we sprinkle our new uh, sort of genetic insights as she's talking and it's awesome. You'll also get a lot of information from Instagram. You know, me personally, I try and put stuff out there as I see problems. So cash con official, k a s h k h A n, official, find me Instagram and you'll learn as we go. Keep on going along. Every time you find something new, we talk about it until you'll keep learning. (43:23): Awesome. Thank you so much for that and for this information, thank you for your passion about women's health and helping them to be healthier. Any last words of wisdom that you'd like to leave everyone with? (43:36): Uh, well, you know, I did say earlier start, right? Mm-hmm . And if you do one thing well, two things. If you do two things today, just to make that commitment, to start and actually do it, sleep properly tonight, sleep on time, have proper sleep hygiene, which means no tv, no laptop, no phone, right temperature, no distractions, good uh, blockage of light. Do that and start making that because that's free and easy. You don't need a doctor's oversight, everything's in your control. Do that now. Start today. Second thing is think about your environmental health as women. Think about how important what you're breathing, what you're eating, and what's coming in through your skin. What chemicals are you using at home? What did you just clean your countertop with? What did you just spray in your lung? Start thinking about that today. If you don't do anything else, do those two things. (44:30): Yes, I think that's wonderful advice and I look forward to hearing from you all listening, which ones or hopefully both that you've done and what changes you're starting to notice. Cuz sometimes it doesn't take much, just small changes. One little step can be so powerful Kashif Khan, thank you so much for joining us today. It was a pleasure. Thank you. And thank you all for listening to another episode of The Hormone Prescription with Dr. Kyrin. I'm so glad that you chose to join us today, and I know that you've learned some new information that you can put into action in your life to start making changes. Like has she shared with us that Seth Godin said, the cost of being wrong is less than the cost of doing nothing. So do something and then reach out on social media and let me know what you chose to do. Thank you so much for joining me, and I will see you next week. Until then, peace, love, and hormones, y'all. (45:34): Thank you so much for listening. I know that incredible vitality occurs for women over 40 when we learn to speak hormone and balance these vital regulators to create the health and the life that we deserve. If you're enjoying this podcast, I'd love it if you give me a review and subscribe. It really does help this podcast out so much. You can visit the hormone prescription.com where we have some free gifts for you, and you can sign up to have a hormone evaluation with me on the podcast to gain clarity into your personal situation. Until next time, remember, take small steps each day to balance your hormones and watch the wonderful changes in your health that begin to unfold for you. Talk to you soon. ► Get your DNA Test Kit and 360 Report: Discover Exactly What Your Body Needs By Looking At Your DNA CLICK HERE. ► Feeling tired? Can't seem to lose weight, no matter how hard you try? It might be time to check your hormones. Most people don't even know that their hormones could be the culprit behind their problems. But at Her Hormone Club, we specialize in hormone testing and treatment. We can help you figure out what's going on with your hormones and get you back on track. We offer advanced hormone testing and treatment from Board Certified Practitioners, so you can feel confident that you're getting the best possible care. Plus, our convenient online consultation process makes it easy to get started. Try Her Hormone Club for 30 days and see how it can help you feel better than before. CLICK HERE to sign up.
Welcome to Episode 109 of the Autism Parenting Secrets. This week we have an amazing guest who provides a compelling, cutting-edge approach that you likely have not heard of. We're talking about genetic-specific nutrition.Our guest is Bob Miller. In 1993, he opened the Tree of Life practice and he has served as a traditional naturopath for 27 years. In 2016, he created an online certification course on genetic nutrition for health professionals now training over 900 health professionals in the program.Bob is the founder and president of Functional Genomic Analysis, an online software program that organizes and analyzes genetic SNPS for functional health professionals across the world.Getting more informed so you can take better actions to support your child and yourself is the opportunity. And the secret this week is…Genes are CLUES, Not Destiny You'll Discover:What is Functional Genomics? (5:00)What The Science Says (7:39)How Mold Wreaks Havoc (14:42)Why You Need To Be Careful With Omega 3s and Fish Oil (18:22)Even More Reasons To Avoid High Fructose Corn Syrup (21:02)The Link Between Inflamation, Histamine and Mast Cell Activation (30:07)What You Need To Know About MTHFR (34:03)The Miracle Molecule (38:54)Minimizing Exposure To Glyphosate Is Essential (41:51)How Glutamine and Glutamate Play A Role (53:58)The 3D Chess Game Played Underwater (58:34)About Our GuestFor the past several years, Bob Miller has been engaged exclusively with functional nutritional genetic variants and related research, specializing in nutritional support for those with chronic Lyme disease.Bob lectures nationally and internationally at seminars to educate health care practitioners about genetic variants and nutritional supplementation for achieving optimal health, and holds live webinars every other Thursday evening for health professionals. In 2016, he created an online certification course on genetic nutrition for health professionals now training over 900 health professionals in the program.Bob is a frequent guest on many podcasts such as Dr. Jill Carnahan, Better Health Guy, Dr. Joseph Mercola, and many others.To support his growing genetic research efforts, in 2015, Bob founded and personally funds, the NutriGenetic Research Institute to research the relationship between genetic variants and presenting symptoms.His first research project on genetic variants in those with chronic Lyme disease, was one of two winners for research by the ILADS international meeting held in Helsinki, Finland. His Phase II study of Lyme disease was presented at the American ILADS conference in November 2016, Phase III was presented at the International ILADS conference in Paris, France in May 2017 and his Phase IV study on mTOR and Autophagy in Lyme disease was presented in Boston, November 2017. Phase V was presented in Warsaw, Poland in June 2018 and his Phase VI was another winner presented in Chicago, Illinois in November of 2018 which showed increased variants in the Heme pathway and Mast Cell genes. Phase VII presented in Madrid, Spain in June of 2019 research showed how genetic variants in genes related to the production of and utilization of NAD+ and NADPH are creating what is now referred to as the ‘NADPH Steal'. In 2020, he presented his research at the online ILADS conference on genetic mutations in the synthesis and utilization of bile.Bob has created 72 nutritional supplement products exclusively for health professionals for Professional Health Products and Functional Genomic Nutrition through Compounded Nutrients. The products he formulated are based upon his genetic research and are designed to support function that may be impaired by genetic weakness.Bob is the founder and president of Functional Genomic Analysis, an online software program that organizes and analyzes genetic SNPS for functional health professionals across the world.Memberships:National Association of Certified Natural Health ProfessionalsAmerican Association of Nutritional ConsultantsBoard Certified Naturopath - American Naturopathic Certification & Accreditation BoardBob MillerTree of LifeReferences in This Episode:Rantes Overview PDF - use this to follow along with the discussionWatch the video version of this presentation hereOmegaQuantDr. Jill CarnahanAdditional Resources:Free Resource: 33 Mistakes Most Autism Parents Make and How To Avoid ThemGot a Picky Eater? - this can helpTo learn more about Cass & Len, visit us at www.autismparentingsecrets.comBe sure to follow Cass & Len on InstagramIf you enjoyed this episode, share it with your friends.Don't forget to subscribe to the show on Apple Podcasts to get automatic episode updates for our "Autism Parenting Secrets!"And, finally, please take a minute to leave us an honest review and rating on Apple Podcasts. They really help us out when it comes to the ranking of the show, and we read every single one of the reviews we get. Thanks for listening!
Sally Mackenzie is one of the world's foremost experts on epigenetics, the study of how environmental changes affect the way genes are expressed. In this conversation we cover an epigenetic techniques she's patented, the biotech company she founded, and the potential role that epigenetics could play in human health.Relevant LinksMackenzie Laboratory WebsiteEpicrop Technologies Inc.Trailblazers: Sally Mackenzie's Vision for the Future of PlantsFeatured GuestSally MackenzieDirector of the Plant Institute; Huck Chair of Functional Genomics; Professor of Biology and of Plant Science
View the show notes on the episode webpage: https://www.bradyholmer.com/pod/46 My guest on episode 46 of the podcast is Dr. Annet Kirabo. Dr. Kirabo is an Assistant Professor of Medicine in the Division of Clinical Pharmacology in the Department of Medicine at Vanderbilt University Medical Center. She obtained her PhD from the Department of Physiology and Functional Genomics at the University of Florida College of Medicine. If you enjoy this podcast and would like a way to support my work, the best way to do this is by becoming a supporter on Patreon, where you can pledge a monthly donation of any amount. You can find more information about becoming a Patreon supporter by going to patreon.com/bradyholmer or finding the link in the show notes. You can also support the podcast through a one-time donation using the links on my website. Just go to bradyholmer.com/donate or check the link in the show notes for more information. Last but not least, if you enjoy any of the topics that appear on this podcast, you will love my Substack and weekly newsletter that I send out every Friday called Physiology Friday. To sign up to receive occasional blog posts and my weekly email newsletter, go to bradyholmer.substack.com/about. If you sign up, I hope you enjoy! Links Episode webpage: https://www.bradyholmer.com/pod/46 Watch the video of this episode (Patreon exclusive until 6/20/22): https://www.patreon.com/posts/67694663 Follow Dr. Kirabo on Twitter @annetkiraboc1 List of Dr. Kirabo's scientific publications on PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=%28Kirabo+Annet%5Bauthor%5D%29+AND+Vanderbilt+University%5BAffiliation%5D&sort=date Read Dr. Kirabo et al.'s paper: “Recent advances in modulation of cardiovascular diseases by the gut microbiota”: https://drive.google.com/file/d/1vIZtuVF1n8C4NbsGGm-Rdk8gFtw47Cdl/view?usp=sharing Support the podcast on Patreon: https://www.patreon.com/bradyholmer Other support options: https://www.bradyholmer.com/donate Listen on Apple Podcasts: https://podcasts.apple.com/us/podcast/science-chill/id1494739189?cc=us&id=1494739189&ign-itscg=30200&ign-itsct=podcast_box&urlDesc=%2Fscience-chill Listen on Spotify: https://open.spotify.com/show/2ilq7P9OBAiqrxk4Ac4WQg Subscribe to my weekly newsletter Physiology Friday: https://bradyholmer.substack.com/about 10% Discount for On brand running shoes when you buy through Suda's Fit Foot: https://www.sudasfitfoot.com/shop
JMCC Social Media Editor Kate Weeks interviews Lucie Carrier, Professor of Functional Genomics of Cardiomyopathies at the Institute of Experimental Pharmacology and Toxicology at University Medical Center Hamburg-Eppendorf, on her scientific career.
Better Edge : A Northwestern Medicine podcast for physicians
Deborah (Debbie) Winter PhD discusses functional genomics for precision medicine in rheumatoid arthritis and scleroderma. She describes recent studies in rheumatoid arthritis and scleroderma using functional genomic approaches to study disease. She explains the various types of functional genomic data that may be obtained from patients and evaluates the quality of functional genomics data to determine its relevance to clinical decision-making.
Fat cells are specialised to store large amounts of fat that act as metabolic energy depots. However, fat cells carry out many other vital functions such as appetite regulation. Fat cells can talk to each other, the brain and the other organs. In this episode, Professor Susanne Mandrup talks about fat cells, as well as the epigenetics and DNA associated with fat cells and metabolic disease. Ph.D. Susanne Mandrup is Professor at Department of Biochemistry and Molecular Biology at SDU where she serves as Director of the Center of Excellence in Functional Genomics and Tissue Plasticity (ATLAS) and Center for Adipocyte Signaling (ADIPOSIGN), as well as Head of the Functional Genomics & Metabolism Research Unit. Click here for more information about ATLAS and ADIPOSIGN.Professor Susanne Mandrup is an elected member of the Royal Danish Academy of Sciences and Letters, Academia Europaea, AcademiaNet, and the European Molecular Biology Organization (EMBO) and Knight of the Order of Dannebrog.For more information about Professor Susanne Mandrup, please refer to the SDU Research Portal.Follow Susanne on Twitter @susmandrupPlease fill out our podcast review form to help us evaluate the season.Follow us and get in touch.Twitter: @Science_Beers, @DanishIASFacebook: @Scienceandbeers, @DanishIASEmail: scienceandbeers@gmail.comwww.scienceandbeers.com/podcastSign up for our newsletter.This season of the podcast is made with the support from the Danish Institute for Advanced Study. Follow their Lecture series.This podcast is hosted by Michael Magee.Cheers to Science! See acast.com/privacy for privacy and opt-out information.
Dr. Mansoor is the President and CSO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing, consulting, and personalized health solutions. Dr. Mansoor is widely regarded as a pioneer in medical genomics and has been the recipient of multiple academic and industry awards. He is the holder of several patents in the general fields of molecular diagnostics and genomics research and is one of the most sought-after national and international conference speakers in the genre of personalized medicine. Dr. Mansoor maintains an active clinical practice as a genomics consultant to some of the leading executive health clinics in Canada and abroad. Dr. Mohammed has served on the Canadian Board of Autistic Research and is a consultant to the world-renowned Toronto Center of Applied Genomics. He is also the Genomicist-in Residence for the Autism Hope Alliance. See the full blog post and transcription here: www.mychildwillthrive.com/vitamin-d-how-genetics-impact-deficiencie
"This is Today" features the stories that make this day unique. It's Tuesday, June 8, 2021, and here is what we talk about today:National Best Friends DayWorld Oceans DayName Your Poison DayJames MadisonGeorge OrwellGhostbustersPensacola, FloridaGuest Penny Riggs Associate Professor of Functional Genomics and Associate Vice President for Research, Texas A&M University Help to support this podcast:Become a Patron!This post was proofread by Grammarly.Subscribe to Learning More Get bonus content on Patreon See acast.com/privacy for privacy and opt-out information.
Thanks for listening and subscribing to Learning More, where each episode brings you a new story about people, inventions, pop culture, and life. In this episode, we discuss mRNA.We are joined by Penny Riggs Associate who is a Professor of Functional Genomics and the Associate Vice President for Research at Texas A&M University.Show LInks:Additional information about mRNABecome a Patron! See acast.com/privacy for privacy and opt-out information.
Biofuels and bioproducts are a way to kick our addiction to fossil fuels. In this episode, we get a peek into how scientists Aindrila Mukhopadhyay and Steve Singer are harnessing the versatile bacterium Pseudomonas putida to break down biomass and help bring about a more sustainable, bio-based economy. They conduct research at the Joint BioEnergy Institute (JBEI), a JGI partner and one of the four US Department of Energy Bioenergy Research Centers. Find more info on this episode, including the transcript, at https://jgi.doe.gov/genome-insider-s2ep3-better-living-through-bioenergy/
This week we welcome Dr. Mansoor Mohammed. Mansoor is the president and chief scientific officer of The DNA Company and is considered to be a pioneer in medical genomics. He’s a classically trained molecular immunologist who has received academic and industry awards, published numerous papers, and holds patents in the general fields of molecular diagnostics and genomics research. In this episode, we discuss the relationship of Functional Genomics and Epigenetics, both informing and transforming information on hormones from genetic testing, and Androgen Dominance and Estrogen Dominance. We also dive into the impact of oral contraceptives and their impact on genetic variances as well as, an in-depth breakdown of the three Estrogens and Estrogen Metabolism. Join The Better! Community On Facebook. Get the show notes here.
Our hormones affect almost every aspect of your body. Mood, metabolism and many physical processes are all governed by hormones. However, you might not recognise just how unique you are genetically. Our genetic profile and predisposition to certain hormones impact our daily lives more than we think it does. Learning more about ourselves can drastically improve our quality of life and allow us to make informed and empowered decisions. Dr Mansoor Mohammed joins us in this episode to explain the importance of understanding our genetic predisposition and the hormone cascade. He also talks about women's hormones. Finally, he explains why we should take our genetic profile into account before experimenting with pharmaceutical treatments and different types of therapy. If you want to know more about the science behind your genetics and hormones, this episode is for you. Hormone Report with The DNA Company If you would like to have your hormone test done, understand your genetics in regards to your hormones and would like to then have these interpreted by Lisa, please go to this link to get the test done. Lisa will then contact you once the DNA has been processed to have a consultation. Please note the consultation will take an hour and will cost $190, which is extra to the actual report. The Report can be purchased here: https://www.mydnacompany.com/products/lisa-tamati-and-the-dna-company-female-hormone-profile Please note The DNA Company is based in Canada and this price is in Canadian dollars. It may take up to 6 weeks depending on where you are located in the world for your results to get back to you. For any questions, please email lisa@lisatamati.com. Get Customised Guidance for Your Genetic Make-Up For our epigenetics health program all about optimising your fitness, lifestyle, nutrition and mind performance to your particular genes, go to https://www.lisatamati.com/page/epigenetics-and-health-coaching/. You can also join our free live webinar on epigenetics. Online Coaching for Runners Go to www.runninghotcoaching.com for our online run training coaching. Consult with Me If you would like to work with me one to one on anything from your mindset, to head injuries, to biohacking your health, to optimal performance or executive coaching, please book a consultation here: https://shop.lisatamati.com/collections/consultations Order My Books My latest book Relentless chronicles the inspiring journey about how my mother and I defied the odds after an aneurysm left my mum Isobel with massive brain damage at age 74. The medical professionals told me there was absolutely no hope of any quality of life again, but I used every mindset tool, years of research and incredible tenacity to prove them wrong and bring my mother back to full health within 3 years. Get your copy here: http://relentlessbook.lisatamati.com/ For my other two best-selling books Running Hot and Running to Extremes chronicling my ultrarunning adventures and expeditions all around the world, go to https://shop.lisatamati.com/collections/books. Here are three reasons why you should listen to the full episode: Understand why it is essential to learn about the nuances of the menstrual cycle. Discover your individuality as a person going through hormonal cascades. Learn more about the effect of estrogen and why being on the pill fundamentally changes you up to the cellular level. Resources Your DNA Company Female Hormone Profile Report In the FLO by Alisa Vitti The DNA Company The DNA Company on Facebook Episode Highlights [06:47] The Journey Going Through Hormones Menarche is the first menstrual cycle, which is when a female enters young womanhood. After menarche comes pre-menopause, perimenopause and then post-menopause. Our sex hormones are fundamental at a holistic, physiological and phenotypic level, as they affect functions at the cellular level. Hormones have a circadian nature, which affects metabolism, oxidative stress and other physiological processes. Some of the top female athletes in the world are still unaware of their menstrual cycles’ health and how it affects them. The phases of the menstrual cycle and variety of hormones affect ligament flexibility, likelihood of injury and exercise response, among others. [12:45] The Circadian Rhythm of Hormones The nuances of your hormonal circadian rhythm rely heavily upon your genetic predisposition. Women have different mental, emotional and physical responses, depending on where they are in their cycle. We should focus on the individuality of women when it comes to the genetic traits of their hormonal circadian rhythms. Females need to listen to their bodies and be wary of one-size-fits-all approaches to hormones such as birth control. The pill can either be a saving grace or bring complications. [18:39] Understanding Hormones, Treatment and Therapies Even without the extremes such as hormonally-related cancers, daily issues such as migraines, fatigue, weight gain, and nutrient deficiencies can occur. Knowing your innate tendencies is essential to feeling healthy and optimal. Most women enter womanhood without clearly understanding their innate patterns. This lack of understanding forces them to accept the routine or resort to pharmaceutical treatment. Symptoms of what was thought of as supposedly lyme disease and other complications vanish when women enter pregnancy. Some hydroxy-dominant women have a genetic predisposition to inflammation and oxidative stress due to hormones, regardless of their diet. [29:44] Estrogen and Testosterone Estrogen is essentially aromatised testosterone. Four hydroxy estrogen metabolites in men contribute to prostate enlargement, leading to inflammation. Men who have a genetic predisposition to aggressively convert estrogen into metabolites are more likely to experience benign prostatic hyperplasia. Both men and women will benefit from understanding their tendencies when it comes to converting metabolites. [35:57] Athleticism, Menstrual Health and Birth Control Some women can eat the same food and do the same exercises but can never achieve the same musculature. World-class athletes need to understand their monthly cycle thoroughly to be in an optimal state. Being on the pill makes you estrogenised for 21 days instead of the usual five days, which can be wonderful or detrimental for you depending on your genetic makeup. Estrogen binding to its receptors radically changes gene expression. Being on the pill fundamentally changes you on a cellular level. The pill can be right or wrong for you; taking it is not a trivial matter. Women aren't designed to be estrogenised continuously in the long-term, as it affects mitochondrial efficiency. [47:46] The Effect of Having a Proclivity to Produce 4-Hydroxy and Being on the Pill Being on the pill exacerbates the effects of having a genetic predisposition to inflammatory and oxidative traits in hormones. Women who already have a disadvantageous genetic profile expose themselves to greater toxicity if they estrogenise themselves non-stop. Estrogen isn't evil, and it keeps us young. However, we have to find a balance. Listen to the full episode to understand the entire process and the chemical processes and genetic pathways involved! [53:32] The Importance of Cellular Balance Cells have other receptors, and there has to be a proper balance and circadian rhythms to have healthy processes. Optimal health comes when the presence of hormones come in optimal waves. There are many nutraceutical or nutritional intake and environmental exposures that can further slow down essential processes. An example is a glass of red wine. If you know your genetic predispositions, you can improve your quality of life. This knowledge empowers us to make choices to either live a healthier life or at least mitigate negative consequences and know our genetic limits. [1:03:57] Hormonal Implications for Men Older men can erroneously assume testosterone is the magic fix to declining sex drive and athletic performance due to aging. However, the reality is that you may have a genetic predisposition to convert testosterone into estrogen and become more estrogenised. These have implications with undergoing testosterone replacement therapy and can undermine your goals. 7 Powerful Quotes from This Episode ‘Your listeners have to understand that the way in which their bodies respond to these hormones define and contribute every aspect of cellular function’. ‘Few aspects of medicine are as boldly innately different as the nuances and the individuality of a young woman's innate genetic control of the circadian rhythm’. ‘It defines why she can eat the same foods, exercise the same as her mate, in fact, exercise more than her mate and be fit and be beautiful and be strong, but never get that cut or that sort of musculature’. ‘When you are naturally menstruating, there's only a window of about five to seven days, give or take, in your 28- or 30-day or thereabouts, where you are in your unit, but recycle that your body is actively producing estrogens. Those estrogens are actively circulating in your bloodstream. And the cells of your body are actively responding to that estrogen’. ‘It's about the balance... A healthy female cell is one that is having, it's a traffic system, and it's one that is being trafficked into it at the proper ratios at the proper circadian pulses and rhythms’. ‘If you do not know these things, you're going to be at risk of using a one size fits all approach that will be beneficial for 10%, 20%, 50% of women, but that most certainly equally can be deleterious for a group of young women, unwittingly’. ‘This is about empowerment, it is the empowerment of being informed — being informed about your unique predisposition. What is your operating manual, making your more normative choices, if you will, of these cascades? And then how do you optimise the things that you want to do and the things you don't want to do’? About Dr Mansoor Dr Mansoor Mohammed is the President and CSO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing, consulting and personalised health solutions. He is widely regarded as a pioneer in medical genomics and has been the recipient of multiple academic and industry awards. He is the holder of several patents in the general fields of molecular diagnostics and genomics research and is one of the most sought-after national and international conference speakers in the genre of personalised medicine. Prior to his role at The DNA Company, Dr Mansoor was also the former Founder and President of ManaGene, CEO of Combimatrix, Director of Genomics at Quest Diagnostics and Director of Research and Development at Spectral Genomics. He continuously maintains an active clinical practice as a genomics consultant to some of the leading executive health clinics in Canada and abroad, has served on the Canadian Board of Autistic Research and is a consultant to the world-renowned Toronto Center of Applied Genomics. If you want to learn more about Dr Mansoor and his work on genetics, you may visit his website. Alternatively, you can check out his Facebook and Twitter. Enjoyed This Podcast? If you did, be sure to subscribe and share it with your friends! Post a review and share it! If you enjoyed tuning in, then leave us a review. You can also share this with your family and friends so they can understand themselves more through learning about their genetic predisposition and hormones. Have any questions? You can contact me through email (support@lisatamati.com) or find me on Facebook, Twitter, Instagram and YouTube. For more episode updates, visit my website. You may also tune in on Apple Podcasts. To pushing the limits, Lisa Full Transcript of The Podcast! Welcome to Pushing The Limits, the show that helps you reach your full potential with your host Lisa Tamati, brought to you by lisatamati.com. Lisa Tamati: Well, everyone and welcome back to Pushing The Limits this week. I have a really super duper interview coming up. I know we say that but are some of the people I have just blown me away. And this is Dr. Mansoor Mohammed who is coming on the show today, that name may ring a bell because documents or has been on the show, I think three times previous to this occasion. And he is one of my great mentors and teachers. And he's one of the world's leading geneticists, and functional genomic scientists. And it's really, really exciting to be able to work with a caliber of men, like Dr. Mansoor. Now, today's subject that Dr. Mansoor is going to be talking about is hormones, hormones and your genetic profile in regards to your hormones. We're specifically looking at the female hormone situation today. But what I do want you to know is that the hormones cascade is exactly the same for me. So a lot—while we’re specifically focusing in on the woman today, and we'll probably focus in on the men on another episode. A lot of what we're saying here will be relevant to men too. And just understanding that you need to know about these pathways, the genetic pathways, before you go mucking around with anything hormonal. And also some of the nutriceuticals that you may or may be taking can also interfere with this pathway too. So this information that's going to be coming out to you today is absolute game changer. Really important for me. I'm on bioidentical hormone replacement therapy, and because I'm going through the menopausal change at the moment, just being transparent. So this information for me has been absolutely crucial because I can tailor my own hormone prescription to my specific genetic needs. And then layering that on with understanding where my bloods are at as well. So it's really really key information. If you're a woman who is on the pill, if you're a woman who's got endometriosis, or PCOS. Or if you're a male who's got prostate problems, or if you're a male who's thinking of going on testosterone replacement, all of these things are really, really pertinent to this conversation today. So I don't want you to miss out. Now do stick around to the end of the conversation because Dr. Mansoor has a company called the DNA, a company which actually has DNA reports. So you can get your DNA tested. If after listening to this session, you are curious about what the heck your hormone pathway is, and how to optimise it, then you can—you know, stick around to the end and check out the show notes as all the links will be in there as well. Before we head over to Dr. Mansoor, I just want to remind you, we have a new system now in Running Hot Coaching, my online run training academy. We have fully personalised, customised run training plans based specifically on your goals and where you're headed. If you want to join us in our company, we would love you to come along. You're going to get a session with me to discuss all your goals and your objectives, to answer any questions around running. And then you would also get a fully—after that consultation has been done, you'll get a video analysis so we can actually look at you running and analyse your running style and help you optimise that. And then you're going to get a fully customised training plan for your specific next goal. Whether that's a 10K or 5K, a marathon, a half marathon, it doesn't matter. We will provide the plan for you which will also include all your mobility work, your strength work, as well as your run sessions. And also guidance around nutrition and electrolytes and mindset, which are very, very important pieces of the puzzle as well. So if you want to check that out, head on over to runninghotcoaching.com. And you can find out all about it or if you've got any questions reach out to me support@lisatamati.com. Also wanted to remind you my latest book, Relentless is available for sale. You can grab that on my website at lisatamati.com along with my other two books Running Hot and Running to Extremes. I'd love you to check those out. If you love some of the content that's been on this podcast, then these books will definitely be up your alley. My latest book is a bit different to the first two, which were my running adventures and all the highs and lows and disasters and successes that I had racing the world's most extreme events on the planet. The third one is really the journey I took with my mum over the last—how many—nearly five years now. After her aneurysm and bringing her back and rehabilitating her. But it's not just a book about rehabilitation. It's about mindsets about overcoming the odds. It's about the mental strength to be able to carry on when everybody's telling you there's no chance and there's no tomorrow. It's a book that will empower, inspire and have some very, very important messages that I'm really, really keen to get out in the world. So please make sure you check that out as well, Relentless. You can find all of those on lisatamati.com. Right now over to the show with Dr. Mansoor Mohammed. Well, hi, everybody, and welcome back. I am super excited once again to have Dr. Mansoor Mohammed on the show today. And Dr. Mansoor is a real repeat offender on the show. I think this is the fourth podcast. You're the only person who's been on here four times, Dr Mansoor so welcome to the show again. It's fantastic to have you back. Dr Mansoor: It's an absolute pleasure. I'm not sure does that mean I have to repeat myself to be understood? Lisa: No, you've got so much knowledge that we have to share with everybody. That's why. Dr Mansoor: Absolute honor. Lisa: So Dr Mansoor, so today, we are going to be focusing everybody on genetics and hormones in particular. And we're going to be focusing in a bit on the ladies, although this is very relevant for the men out there too. So don't turn off if you're a guy and just go ‘Well, this is for one for the ladies’. This is also aimed at men. But Dr. Mansoor is a world leading functional genomic scientist. And we're going to be talking today about the hormone cascade and understanding our genetic pathways that we take with our hormones and why we need to understand this and how important it is for us. So Dr. Mansoor where shall we start with this journey of going through the hormones. Dr Mansoor: I think the first thing we want our listeners to understand and it's not lost in any young woman, post menarche. And so let's just define just two quick terms menarche, the time in which a young woman begins a monthly cycle and she enters into young womanhood all the way through menopause, pre menopause, perimenopause and then postmenopausal. But in all of these wonderful stages of a young woman's life, that there's what we call sex hormones, the steroid hormones, the progesterone, the androgens, most notably testosterone, estrogens and their respective metabolites. They influence the human body at a cellular and at a holistic level, in the most fundamental of ways. Okay, so that's the first thing. Just to emphasise the importance of these sex hormones. The second is to clarify that with this importance, it's not just about external female characteristics of breast developmental, hip flare or thigh developmental, bum developmental, factor position. It's not just “about the obvious phenotypic or physiologic manifestations” of these hormones. We have to understand that sex hormones impact every aspect of cellular behaviour. These hormones when produced—and by definition, hormones are messenger molecules that are produced in one part of the body. In this case, for example, the ovaries. They then enter into the bloodstream, circulate throughout the body, and then impact every cell in that cellular behaviour. So the second more important point is our listeners have to understand that the way in which their bodies respond to these hormones define and contribute to every aspect of cellular function, every aspect of cellular function. Now, if we can appreciate that. The third thing we've got to appreciate and the young woman’S body, okay, is that there's a circadian rhythm or circadian, generally speaking, that there's a circadian nature to these hormones. In other words, it strikes me and I attended a remarkable conference a bit over a year ago. It was with the Red Bull team of super athletes and their clinicians. And one of the clinicians, she is from the UK. She specialises in treating female athletes. That's her series dealing with female athletes. And in her presentation, we were all presenting at this conference. She said something that was alarming, heart wrenching, but almost not surprising all at once. And what was she said, she would run a survey on these female athletes. These are like Top of the World female athletes, one of which just to begin with was one of the top—if not the top—female soccer teams in the world. And she said, not a single one of these athletes, female athletes were ever asked or made aware of the health of their monthly cycle. Lisa: Wow. Yes. And these are the top people let alone the other... Dr Mansoor: Yes, and so she was beside herself as a scientist and the clinician, that for something as fundamentally impactful to the human body, as those sex hormones. So for example, as she illustrated, depending on whether a woman is in her follicular phase or her luteal phase of her menstrual cycle, proclivities to injuries change, the flexibility of the ligaments, and the body changes, the response to the body to different types of motifs of exercises, changes. When is the female body—can we speak in here, at first, in generalities of the average female going through a monthly cycle, not yet on the pill, we're going to talk about the pills as a separate factor. But just is part of the normative circadian rhythm of the female body. The female body morphs physiologically, cellular metabolically at day seven of the monthly cycle is completely different. And that's speaking a little bit extreme as to the body when it's on day 15, as to the body when it's on day 20. And so you've got individuals demanding the very best from their body optimal performance. And they have not yet even come to terms with the baseline changes to the body between these stages. And as you pointed out, so many injuries due to training in these athletes, and again, we're speaking of athletes, but we can, we can juxtapose that. Like you said the average female trying to simply be the best version of herself, could be avoided. If the young woman only knew what stage in her monthly cycle she was at. If the young woman only knew the oxidative stresses that are different during different times of the monthly cycle. So if I told you Lisa, that at a point in your menstruating cycle, you innately, naturally have surplus, oxidative stress. It really doesn't take a lot further to grow to understand in those times and days, the last thing you want to do is go—there you go. You don't want to put even more oxidative stress at that point in the body. And so on, and so on, and so forth. So in this third category, as you said, to establish the baseline that we're speaking of, we've got to understand the importance of hormones, we've got to understand that it's beyond just the outward superficial physiology of the body. And in this case, speaking of young women, we've got to understand that there is a circadian rhythm to these hormones. Now, once we understand these three bases, these three points,then we have to appreciate that part, a significant part of what controls, that's the circadian rhythm. And then within that circadian rhythm, what controls the nuances of one young woman versus the other relies upon their genetics. Lisa: The genetics, yes. Dr Mansoor: And so once we understand the functionality of the circadian rhythm of the female cycle, Lipson, once we understand the gears that are going through those 28, approximate dates, once we understand that rhythm, we understand the genes that control or significantly contribute to that rhythm. We understand that each individual potentially has variations in those genes that controls that rhythm. We begin to understand the nuances. We begin to understand the individuality of Paula versus Lisa versus Joanne versus Isabel. And so we begin to understand that one aspect of every aspect of intelligent medicine. But few aspects of medicine are as boldly innately different as the nuances and the individuality of a young woman's innate genetic control of the circadian rhythm. And one week we will talk about this, we need to appreciate this. And the most abhorrent of complications that occur, if you do not understand this individuality, one young woman to the next, and then you take that birth control pill, I am not, of course, I have no place to be anti birth control, but I'm a man. I'm not a young woman. Now. So this is not about being controlling. No, not at all. But it's the fate. The simplest thing that we think that you can take 1000 university young woman, you know, first year university students, girls, young woman. And somehow put them on the same birth control, literally the same birth control. And somehow expect that they're getting to be the same effect, and somehow minimalise and even criticise a young woman who comes back and says, ‘I find that I'm gaining weight. I find that I'm—my mood is not the same, I find a’.. And then because five other young women don't have those issues, the doctor says ‘No, that's not because of the pill’, and they are dismissed. And they're not even appreciated as to the uniqueness of their body's response to something. Again, sometimes the pill is a saving grace for a young woman. But what we're speaking of here is in these three pillars, the fourth pillar is the individuality of the genetics of that young woman. And all of the remarkable insights that a young woman can gain from this. Before I go any further, it's not a plug in the least I hope I'm not, you know, going against any regulation of your podcast, but there’s a brilliant book called In the FLO. Lisa: In the FLO. We’ll put the link in the show notes. Dr Mansoor: I have no association with the author. But it's just she did an amazing job. And I'm trying to get the name as I'm speaking about. I'll remember the name. She did an amazing job, without the genetics, of showing how radically important a young woman understanding her circadian rhythm, how different points of her month, her body responds to different foods differently, her brain response, her emotive response. She's really done a beautiful job of highlighting the awesome, holistic cellular changes that go through a young woman's body in these waves of human rhythms every 28 days. So this sets the stage Lisa, everything that we might want to talk about, is predicated on this understanding. And then the genetics that explains this. Lisa: That’s a beautiful entry into this whole actual looking at the mechanics, if you like, of the genetic pathways that I do want to get into. Because in other words, every single woman is individual. And this is the beauty of genetics in general, is that we can actually personalise once we understand their own genetic pathways. And you know, we do this both in our profession is to understand what our genes are doing and how they're expressing and how we can optimise these genetic pathways, if you like, in this case, with our hormonal pathways. And this has a real implication when it comes to things like the birth control pill, when it comes to—In my case, bioidentical hormone replacement therapy on the other end of the scale going through the menopausal years. Because this has implications whereas, you know, if I take biological hormone replacement therapy, and we've actually talked briefly on one of their podcasts about some of my hormonal which I'm happy to share as well. I'm on a hormone replacement therapy. But I understand my genes, and I understand where my problems may lie. And therefore I can keep an eye by from a blood perspective, you know, keep an eye on my hormone levels, but I understand my own cascade. And I can mitigate the chances for example of developing estrogen-based cancers or, you know, like breast cancers or cervical cancers. Whereas another person, if we put them on the same regime may run into trouble. Dr Mansoor: Indeed, even without the—shall we say, more extreme outcomes or concerns, such as hormonally-related cancers, but really just even the day to day well being of the body. You know, the risk of peripheral neuropathy is, the risk of migraines or lack before resolving them fatigue, weight gain, things that are—the way your body responds to nutrients. Again, understanding where your body innately, your your innate tendency is, as per explained by your genes. And we'll get into some profound examples of this. And then making sure that you act in accordance because we have choices. And some of the choices we can make. And sometimes there are, you know, I think there are many times we speak about human optimisation.There are certain voices, and they have a point that can say, ‘Look, but there are universal truisms’. They're just things that we should all know, are either healthy or unhealthy. And there are a few of these things... But what is remarkable here is, especially when it comes to female hormones, there are things that you might deem to be universally healthy, but actually can be either unhealthy or certainly not optimal for some young woman versus others. So we’re really in the realm here of not just talking about universal truisms that are relevant with or without genetics. We're speaking of nuances that are so radically important. And may I say with that, if it's okay with you. I'd like to then set the stage of some of—just set the stage for themes, themes that your audience, your listeners. And then I'm going to say a few things. And my hope, and my goal is, for many of the listeners out there, at least a few of these things should resonate. For example, how many young women out there find that their introduction and their experience to cyclical migraines kick in post puberty? In other words, here she is, she's living in the same home, same nutrition, healthy, or whatever version of lifestyle, and the day comes where she enters into your womanhood and break there after, right there after. Not directly related to her flow as per what she could physically and visually manifest. But this concept of now dealing with migraines, a concept of dealing with a circadian rhythm to her mood, and to her what she might find trouble for those first few years until she becomes an adult woman. And she's got life experiences, but she's always found that she's having a hard time to express, that she literally feels that her emotional resilience, that ability, that barometer to what tips are over that scale of resilience changes. And she's never—and no one has even asked her by the way. ‘Do you see that it comes in patterns? Do you find that it happens? And kicks in three to five days prior to your cycle? Do you find that that's when you see some of these changes in the month? Do you find that it kicks in a day before ovulation? Do you even know when ovulation is happening’? None of these conversations are going to happen. So that these apparently unrelated just symptomologies of ‘Well, there's some anxiety’, or you know, ‘I get migraine’. They just brushed under the growing list of things that ‘Will you just take a pill for it’? Meaning a pharmaceutical treatment. Or they're minimised and somehow they're accepted as just a routine part of all, that's what it is to life. Okay. Or how many young women out there have dealt with some of the symptoms of migraines or pain, Fibromyalgia-like pain, debilitating fatigue. And then something miraculous happens. When they become pregnant for nine months, most of all, have their symptoms resolved. How many young women have said to me, I can't tell you, Lisa. Again, I know that being in New Zealand, I'm not sure if you have to deal with the plague of Lyme disease. It's something that we have here more in Eastern America. Lisa: Yes, more overseas. Dr Mansoor: But yes, but it's a bacterial tick borne disease that ruins lives. And there are, interestingly, a preponderance of women who present with Lyme disease-like symptoms. Now, we worked, I worked in a clinic and I was one of the first to describe this phenomenon. And I had to say not trivialising the horridness of disease, I said to a patient, I said, ‘You know, those ticks don't like women more than men’. Lisa: Then why more women are presenting with these symptoms? Dr Mansoor: Presenting with the symptoms. Unless women were more likely to go trekking and hiking and be exposed to, you know. But here's the point. It was that there was a significant—in one of the clinics that we did the study in. There were a significant number of women who presented with classically, what outwardly seemed as Lyme disease symptomologies of debilitating fatigue, almost concussion-like presentations, mental malaise, muscle aches and pains, as I mentioned, Fibromyalgia-like presentations, and they were convinced that they had Lyme disease, convinced that they had Lyme disease. And because it's such a polymorphic disease, yet many doctors were going ahead and treating them with massive antibiotics, even if they couldn't confirm the Lyme disease. Because many doctors, almost agreeably have had to say because so many, so many true Lyme patients are being under cared for, right that there are some really good doctors wanting to do the right thing, who were treating the symptom and the presentation, per se. But amongst individuals were a preponderance of women who were not testing positive for Lyme disease. So what was going on here? And what we did when we studied these young women was, we looked at a significant number who then went ahead and became pregnant during their proposed Lyme disease. And for the nine months of pregnancy, all of their symptoms resolved. And I had to say to both the doctors and the patients I said, ‘Your Borealis, the burgdorferi Borrelia bacteria, the bacteria that causes—that doesn't just take a hike during pregnancy’. Lisa: It doesn't just go away. Dr Mansoor: It doesn’t just go away. It's not that. So what else is at play here? Well, how many young women understand that during their menstruating months and years, the primary estrogen in their body is estradiol? During pregnancy, your primary estrogen is estriol. Estriol is not metabolised into the same byproducts as estradiol. Estradiol can be metabolised. Every young woman metabolises this estradiol into three byproducts, 2-hydroxy estradiol, 4-hydroxy estradiol, 16alpha-hydroxy estradiol. Now every young woman produces all three. But genetically, you are predisposed to producing more of one or the other depending on your genetics. And if you happen to be the young woman who was predisposed to producing in the ratio, more than 4-hydroxy or even the 16alpha-hydroxy, and God forbid more of the following 16 hydroxy as compared to the 2-hydroxy, the 4-hydroxy. And to a degree, the 16alpha-hydroxy metabolites are particularly inflammatory. They're literally inflammatory metabolites that the body has been designed to get rid of. But if you were that young woman that genetically, was predisposed to producing more of these naughty metabolites, as opposed to the much, much less inflammatory two hydroxide. Then just innately, you the young woman that recycles the body, when it comes around to the body metabolising, those estradiol, your primary estrogen when you're menstruating. When that estradiol is metabolised for a period of two, three to five days, depending on your particulars, your body, literally, regardless of whether you were eating organic and living organic and breathing the best hair in the world, normally, you are producing an internal inflammogen. An internal thing that is causing both inflammation and oxidative stress. Now, during pregnancy, when you become estriol dominant.. Lisa: You're not getting it. Dr Mansoor: You don't get these metabolised. And so when a young woman gets pregnant, and she complains prior to pregnancy, of these malaise and the symptomologies and then comes pregnancy and the only thing that has changed, and I've had young women cry in my office saying ‘Dr. Mansoor, how did you know to ask me if I felt better during pregnancy’? Because usually it's quite the opposite. People think, ‘Oh, my gosh, I'm gonna get morning sickness. And I'm gonna’... These young women were better off. And they would say, ‘You know Mansoor, wish I could stay ‘pregnant. Those were the months where I actually had a relief from symptoms’. So this is Lisa... Lisa: Yes. Sorry Dr. Mansoor. So these 4-hydroxy in the 16alpha-hydroxy to a lesser degree, because it's a rarer situation. And this is in relation to the Cyp19a1 gene, the aromatase gene, turning our testosterones into estrogens. Is there any—so when we go on that—if we put on the pill, which is got estrogen in it. And you're one of those women who have—and this goes for me too. My husband has a 4-hydroxy dominance for example, which is a problem. He is—are we exasperating the problem when we take the pill without knowing it? Dr Mansoor: So just to clarify and add a layer of clarity. So estrogen and the estrogen molecule and the estrogen hormone is actually nothing other than aromatised testosterone. So a lot of young women don't appreciate that, you know, they self identify with estrogen. You know, women tend to self-identify their estrogens, and men tend to “self identify with testosterone”. In fact, I had one of these absurd pop ups on—I was watching a food vlog which is my guilty pleasure, especially doing COVID. I like watching it, you know, foods being prepared and you've got these annoying YouTube ads that come up. And what if it was this buffed, you know, male trainer and he comes on the screen on the ad and he goes, ‘Well, testosterone is what makes a man, a man’. Not quite. But the point is, men need to understand that we too, make estrogens. And women need to understand that the very estrogens that they may or may not self identify with are really simply testosterone molecules that had been aromatised. Okay, so there is a gene, a specific gene, one gene Cyp19a1, as you have mentioned. And in fact, the parlance, the more common name for the Cyp19a1 gene is aromatase. And this gene with its enzyme chemically changes testosterone into estrogen, i.e. estradiol, estriol, as the case might be, okay. But then once you make your estrogen, your estradiol, let's just fix it at that. Then there are other genes that make other enzymes, that make the two or the four or the 16 byproducts. So specifically, there's a gene known as the CYP1B1, CYP1—Bravo—1. This is the gene that makes the self named enzyme that takes some of your estrogen and turns it into the naughty, 4-hydroxy estrogen metabolite. Now, the point here is different women and different men—and just to clarify for the male listeners out there, if you would think that estrogen was a female issue, and if you would think that 4-hydroxy estrogen was a female issue, think again. And we now understand that 4-hydroxy estrogen metabolites in men contributes to prostate enlargement, contributes to the inflammation of the prostate for many years. In fact, for the last two to three decades, all of the research on benign prostate hyperplasia in men has focused on a testosterone metabolite, known as DHT. So DHT, dihydrotestosterone is the product, it is the metabolite of testosterone produced by the steroid five alpha reductase to the SRD5A2 gene with its enzyme produces that metabolite. And it is true, the DHT, one molecule of DHT has the potency to bind androgen receptors as six molecules of testosterone. It's a much more potent, super testosterone. Super, right. So here's the thing. DHT is to testosterone. As 4-hydroxy, estrogen is to estrogen. DHT is the testosterone metabolite that interacts with the androgen receptor, much in the same way as the 4-hydroxy metabolite of estrogen. 4-hydroxy overproduction and men, we have now discovered is a significant contributor to the etiology and the progression of prostate and benign prostate hyperplasia. Lisa: I thought it was just a SRD, the DHT so I need to know. Yes, okay, I need to go and check that with my husband. Dr Mansoor: Now for the last couple of years. Some of the actual pharmaceutical clinical trials to treat benign prostate hyperplasia has switched everything, all of our propecia and finasteride, these medications that we currently... And just for the male listeners out there, it is unsurprising that the very medications that are often used for benign prostate hyperplasia, were found or would then use for balding. It has the same DHT that promotes male pattern balding is the same testosterone metabolites that over inflames the prostate. But now we understand that the males who have the 4-hydroxy estrogen preponderance genetically, why? Because they had a version of the CYP1B1 gene that made a version of the CYP1B1 enzyme that is more aggressive at converting estrogen into this metabolite. So men, this discussion is equally important to you. But coming back to the females very quickly, then Lisa. You see a young woman who does not know who's going about her, you know, her life and her teenage years and her 20s not even knowing ‘what is the degree—what is what is my innate tendency within which I convert my progesterone to testosterone? What is my innate tendency to convert testosterone to DHT? That more virulent testosterone? What is my innate tendency to convert testosterone into estrogen? And by the way, once I make the estrogens? What is my innate tendency and converting it into the twos and the fours and the 16 metabolites’? Because you see, if a young woman were to understand this right off the bat looser, it defines why and how easily she develops lean muscle mass. It defines why she can eat the same foods, exercise the same as her mate, in fact, exercise more than her mate, and be fit and be beautiful and be strong, but never get that cut or that sort of musculature. As for not saying that that's what she wants to know. But so many women are going ‘I work so hard. I trained my bum off but I'm not seeing that type of’, this is going to be intimately described by the woman who is making less DHT from the testosterone, making more estrogens from making more 4-hydroxy estrogens from her estrogen from her testosterone. This is a young woman whose cellular level is estro dominant and estro toxic. And she cannot until and unless she appreciates this. And until and unless she takes steps to reduce. And of course, that's the million dollar question, ‘Can we take us to 37:00 reduce it easily’? And the overwhelming answer is, ‘Yes, we can’. Okay. But she's even unaware of this to take the steps in the first place. So let me come back to those super athletic young females for whom their doctor, when they did the research. Here they were, no one ever even asked them what their monthly cycle health was. ‘Are you having a monthly cycle? Is it irregular? How do you feel with the cycle? Are you on the pill’? So now I answer your question, you see Lisa, if you didn't know where you were innately on that cascade. Remember, young woman out there, all of the ladies out there, in a ‘normal’, in your natural monthly cycle, without the pill. You know, just you're 16, you're 26, you're 36 you're menstruating. How many of you realise that that estrogen that you self identify with isn't produced 24/7, 30 days a month? Lisa: Exactly. It is when you put on the pill work. Dr Mansoor: That's the difference isn't it? The very point that I'm trying to make is, in your natural monthly cycle, your body is only estrogenised, it is only under the influence of this hormone. And I'm going to stop beside and make a couple more points on this. But I'll finish my point here. When you are naturally menstruating, there's only a window of about five to seven days, give or take in your 28 or 30 day or thereabouts, where you are in your unique monthly cycle, that your body is actively producing estrogens. Those estrogens are actively circulating in your bloodstream. And the cells of your body are actively responding to that estrogen. Compare and contrast that to being on the pill, where have for 21 days of a 28 day cycle, not five to seven days, 21 days, your body is under the influence of testosterone. Here's the thing Lisa, that I have to admit. And again, let me be clear, all of Lisa's amazing listeners, this is not about anti-pill. The pill is absolutely—it is your right. It is something that you control. It is absolutely a godsend for different times of your life and for different young women. But you've got to ask, Where are you in the spectrum of young woman? And how will your body respond to this differently? And you would at least need to understand that your body was not estrogen eyes for 21 days in your normal cycle. And here's the newest thing, Lisa. That I must admit, this gives me indigestion. Again, I have no say over the matter, but down the practice of actually having no bleed, how many women are now being put on constant pill without even a bleed through? So now you go from a normal physiology of every month, say seven days of estrogenisation to 365 days of estrogenisation. Lisa: Disaster. Dr Mansoor: So now, Lisa I'm—and we would be remiss if I don't quickly emphasise to our listeners, what is estrogen? ‘What is this thing that you—okay, well, it's stopping me from getting pregnant. My hair is luscious, my skin might look really wonderful. So after all, shouldn't be a problem’. What you have to understand, and our listeners out there in the female body—and I can speak of the male and female body, I'm just going to focus on the female body for the time being. In the female body, Lisa, every single cell produces these receptors for estrogen. So if this is your cell, you have an estrogen receptor. And when that estrogen is produced, or it is taken as a pill, or as whatever the— even certain neutra estrogen analog or xenoestrogens and plastics, these molecules enter your body, they bind to these receptors on your cells, okay? Because by the way, estrogen doesn't do what it does in the body by just being produced and floating in the bloodstream. No. Estrogens do what they do in the body by being produced by then binding to these receptors. And what happens, this is the important point. What happens when estrogen binds to its receptor? What happens is the DNA expression, your genes in that cell, gene expression is radically altered? Literally, the genes, the instructions within your cellular operating manual changes when estrogen enters the cells. When there's no estrogen in the cell changes. So now let's come back, the female body.. Lisa: Apologies for the phone call people in the background. Dr Mansoor: The female body in its normative circadian rhythm experiences a gene expression shift, change in gene expression for the days in which your estrogen was elevated. And yet, of course, it comes back down in the normal cycle. What happens when you force yourself to go into a gene expression shift to 365.. Lisa: Constantly. Dr Mansoor: ...days a year without change. Lisa: And we're talking like hundreds of genes, hundreds of thousands of genes that have been changed, turned on and off, turned on, and wow. Dr Mansoor: These genes impact the metabolic efficiency of your cells. Well, the thyroid function, which is why how many times we see a competitive joint problem between hypothyroidism, hyperinsulinemia—your body's response to insulin, and estrogen dominance. Wow. And when these three things come together, we euphemistically call it metabolic syndrome. You know, there's a read, there's a point behind, there's an impact behind it. And the point here that I want to make is, we often just think of the sometimes and arguably beneficial outcomes, outward outcomes of being on the pill. Okay. And I emphasise for the umpteenth time, please, this is not about not being on the pill. The pill can be what is right for you at certain points in your life. But it's about being educated, that taking this hormone is not something as trivial as stopping your ovaries from producing an egg. That's not what that hormone is doing only. This hormone is interacting with every cell in your body and it is changing the way your genes express in every cell of your body. Now, the point here is, if we were to do—I like to call it a heat map. If you took a young woman, and you colour code her body, from white to red, according to which cells in her body have had more estrogen receptors. What you will do is the whole body isn't going to be white, the whole body isn't going to be red, it's going to be shades of white and pink and red. And of course, unsurprisingly, the region of the breast tissue will be somewhat the reddest, because those cells and the breast tissue are some of the most sensitive to estrogen. So what does this mean? It means that when estrogen is present in the bloodstream, the cells of the breast tissue are some of the most able to absorb that estrogen. But what happens when it absorbs the estrogen? Gene expression happens, gene expression changes happens. And the cells were designed to account for a circadian rhythm to their gene expression change. Not 21 days, repeatedly, repeatedly, or 28 days, for that matter, repeatedly, repeatedly. Again, I stress not for the young woman who is seeking birth control maybe for a few months, or periods in our life. We're speaking of the travesty of the young woman that had been on the pill since they were 14. And here they are 32. Lisa: Unable to conceive and or cancers, or weight gain, or cellulitis, or all of these implications. Dr Mansoor: The very metabolic machinery of that cell, you're very mitochondrial efficient efficiency of the cell is impacted during—and this brings me back to the brilliant comment by the brilliant female scientists that I was speaking of earlier, where a young woman should understand that in her natural, healthy 28 day rhythm, metabolic efficiency, mitochondrial efficiency, changes in response to the ratios and the waves and thrusts of progesterone versus testosterone versus estrogen. Think what happens when you put a blanket of estrogen over everything, 24/7, 28 days, 30 days a month, 365 days a year. Now, the point here, Lisa is coming back to even more finesse point in your question is, well, that is what I what we've just explained happens in every young woman that goes into pill, every young woman that goes into pill. But what happens when you didn't realise that you had the proclivity of making more of the 4-hydroxy estrogens? What happens when you didn't realise that your ability to then neutralise the 4-hydroxy estrogen that inflammatory estrogen metabolic, which by the way, you know, not realising that you were making more of it. You were producing—when you introduce X amount of estrogen molecules more if it was going down the 4-hydroxy pathway than the healthier 2-hydroxy pathway? If you were not aware of this, and you were doubly unaware of the molecular mechanisms that neutralise? So what is the gene? — Let's take a look at this. What is the gene that neutralises 4-hydroxy estrogen? What is that gene? The gene that neutralises, is COMT, catechol-O-methyltransferase. This is the gene, the gene that is—makes an enzyme. The same name, that's COMT enzyme. And the job one of the jobs of this enzyme is that it recognises the production of 4-hydroxy estrogen, which is inflammatory, which is pro-oxidative, pro-inflammatory, pro-estrogen. Indeed. Because here's what happens, that 4-hydroxy estrogen—think about it, Lisa and all of the listeners—you took estrogen, which was binding to its receptor, and causing all of those estrogenised changes that we spoke of. So of course, what the body wants to do is it wants to limit the duration by which estrogen can bind to its receptor. So it's good to metabolise the estrogen. But ironically, when you metabolise your estrogen into 4-hydroxy, estrogen, ironically it's still doing—in fact, not only is it still binding to the estrogen receptor. Some studies indicate it can bind to the estrogen receptor actually with greater proclivity within greater binding efficiency than its original estrogen. And it can induce that altered gene expression 2-hydroxy estrogen does not do it near as much, which is why we consider the 2-hydroxy estrogen prefer—to be the best pathway. Well, the point here is COMT converts that full hydroxy estrogen into 4-methoxy estrogen. Now, 4-methoxy estrogen dramatically loses its ability to bind to the estrogen receptor. So 4-methoxy estrogen is what we can now say it's no longer estrogenising. Okay? The other thing of the 4-hydroxy, going back now to the 4-hydroxy, estrogen, if you're not removing it, if you are not converting it by methylation into the methoxy, estrogen, 4-hydroxy estrogen, it decomposes into these nasty little molecules called quinolones. Horrible, not very nice things. And quinolones decomposed into oxidants. So the whole stagnation if—let's let's clarify the statement now. Now, if as a young woman, you did not know that you have the predisposition, when ever your body sees estrogens, whether they are internally made, or externally introduced, when ever your body sees estrogen molecules, if you did not know that you A) tend to metabolise those estrogens into 4-hydroxy by products more than we would like and B) you will not as efficient at neutralising the 4-hydroxy estrogen by virtue of COMT, what you are unaware of is you are unaware of this thing called an estro dominant burden with estro toxicity. You are unaware that in your normal cycle for five to seven-ish days, your body is under the strain of an internal inflammatory production, internal oxidative stress more than your female companions. And will you to then take that normal exposure, but then by going day in day out on an estrogen source, think of what you're doing to the body. Lisa: And by the same take of the bio identical hormone replacement on the other end of the scale with the menarche, the menopause. And we want like, just just to clarify, estrogens are not evil things we want. The body needs estrogens and like it keeps us younger. I mean being on—this is the dilemma that I've been facing. The biological hormone placement keeps me—my bone density good, keeps me—you know, being able to hold my muscle, my skin is better. I'm not aging as quickly the inability or cells of my vessels are better, etc, etc. However, I need to keep those in a balance so that I don't get too many chicks estrogens going in or I need to keep my progesterone up and I need to make sure I know where my testosterone is. Yeah, so that. Dr Mansoor: Because it's about the balance. It's about finding—and so here's that final point. You know how we spoke about the cells, Lisa having these estrogen receptors? Well, your cells have androgen receptors as well. And they have progesterone receptors as well. So think now, we can almost visualise a healthy soul, a healthy female soul is one that is having—it's a traffic system. And it's one that is being trafficked into it at the proper ratios at the proper circadian pulses and rhythms. Sometimes estrogens are getting in, altering gene expression in an estrogenised manner. Sometimes androgens are getting in altering the gene expression in an androgenised manner. Sometimes progesterones are getting it, altering the gene expression and the progesterone alised manner. And it is optimal health and optimal youthfulness and responsiveness to yourself is when we get that circadian rhythm allowing the cell and allowing its operating manual, its genes to go through this rhythm of when are the—the genes that are controlled, and that are going to be expressed because of the presence of estrogen. The genes that are going to be controlled and expressed because of the presence of testosterone, because of the presence of progesterone, these waves and rhythms of gene expression, optimal health is when these waves happen in the optimal full manner, okay? And we can replace that optimality and we can extend the optimality and therein lies the brilliance of hormone replacement, of which it absolutely is something that you know, other knowledge can afford. But unfortunately, when we do this, without the appreciation of the individuality of these ebb and flow waves, and we push the system, without appreciating what was the a priori tendency of that young woman. Was this young woman a priori andro dominant? Was she a priori estro dominant? Was she estro toxic? Was she estro dominant and estro toxic? If you do not know these things, you're going to be guilty of—you're going to be at risk of using a one size fits all approach that will be beneficial for 10%, 20%, 50% of woman, but that most certainly equally can be deleterious for a group of young woman, unwittingly. Lisa: And this is what shocks me is that we have done this human experiment, like 85% of the population of woman on the planet who are in their menstrual years have been on or are on the pill, including myself, who was on it for 25, 30 years, I don't even know and ended up with fibroids, ended up with endometriosis, even though I don't have the 4-hydroxy dominance. Yes, and because I was constantly on these things, and so now with these genetics—and this is the point. We are able to tweak into change. For example, I'm on organic black seed oil, which upregulates my Cyp18a1 genes, which helps me create more 2-hydroxy because I'm 57:15 red-lighted if you like for that one as well. I take them so that I can slow down the aromatase of testosterone. I have a very quick Cyp17a1. So I need a bit more progesterone support, because I'm making my testosterones very quickly. But without this knowledge, we just like throwing mud against the wall and hoping it sticks in the right places and doing so many people and injustice. Dr Mansoor: Think about this, Lisa, that COMT, that all important—that is that is methylating those metabolites including the naughty 4-hydroxy estrogen. Well, Lisa and listeners out there, there's a variation of very, very, very well studied variation of that come to genome. For those of you who are dabbling with a little bit of genetics, this is the rs4680 variation. So you can actually go look at the code of the variation. And these variations have coding qualifications. This is the rs4680 variation. And this variation is defined by two alleles, two versions of the gene. One is a G version, G as in George, the other is the A as in apple version. Okay? Now, the G version of this gene produces a version of the enzyme that is faster, it is kinetically more efficient at doing its job. But what is it one of its jobs? Neutralising 4-hydroxy estrogen. So much so that if you were a GG, both copies of your comt with the fast versions, the genes and versus if you were AA, both versions were slow. The AA COMT individuals, the people that have to have the slow versions of the gene, their COMT is working at 70% to 75% slower than the person that is... We're not talking trivialities, we're not talking 5% to 10%. We're saying that if you're an AA, your enzyme is doing the job. It's doing its job. It's just doing it 70% slower than if you were a GG. Now, here's the point. If you were a COMT A and you had the fast version of Cyp1B1 making more 4-hydroxy estrogen from whatever estrogens your body is seeing. Now you’re not getting rid of it. And here's the final point. There are a number of nutraceutical nutritional intake things environmental exposures that can further epigenetically slow down COMT. So here's one of them. Several of the molecules, the phenolics, in red wine, which we could talk about whether red wine is good for you one glass, we can… But the phenolics in red wine epigenetically slows down COMT further. If you were in AA COMT, already dealing with a pump enzyme, it is doing its job. And then you will drink something like red wine that another person might have had, you know, perfectly fine having a glass of wine, or whatever the case might be helpfully. You don't even realise that you're doing something that is actually now nutraceutically—from a nutrition perspective, working against something in you that you were even unaware of. Lisa: Wow. And then if you layer on that, that you don't have optimal B 12 levels and folate levels and your methylation process is slow. Dr. Monsoor: Now we're really putting in—you're really putting fuel on the fire. So those listeners out there... Lisa: Yes, this leads to things like cancer. Dr. Monsoor: It leads to cancer, it leads to—again, I keep saying, you know, even before we get to cancers, it leads to a quality of life, that can be so radically either improved if we knew or simply a quality of life, where we're simply being told ‘Well, you know, that's just of the things… That's the way it is’. Lisa: Wow, Dr.Mansoor, I know you've got another appointment coming up, and we have to jump off the call. And I don't really feel like we've finished this conversation. So again, I'm going to have to have you back. And we have to go over the men’s male hormone report too, because everything that we've seen today is also valid for the men in different races, same cascade. And what I want to get across though, Dr. Mansoor is that you have the power now to be able to understand these genetics. So you and the DNA company have a hormone report, which I'm going to link to in the show notes that people can go and order. The only reason I'm doing this is because I want people to get this report. I want them to understand the genetics and I want them to optimise the genetics and make informed decisions around their hormone replacement or their pill or their what nutraceuticals to take, whether you should take them with you should take black organic seed oil, goodness knows what—all of these things that we can do to optimise our pathway. So I'm going to be linking to that in the show notes that Dr. Mansoor's company has this report now. And you can find out exactly what you should do and how to optimise your your actual personal hormone situation. Dr. Mansoor, is there anything you wanted to add there? Dr Mansoor: Well, Lisa, shortly, the short answer, no. A little longer than the short answer is to emphasise what you've just said. This is about empowerment. It is the empowerment of being informed, being informed about your unique predisposition. What is your operating manual, making your more normative choices, if you will, of these cascades? And then how do you optimise the things that you want to do and the things you don't want to do. And it is this empowerment that we really want. It's not about negating any choices you have. It is rather simply about empowering you to either make healthier choices, or when you make certain choices, you make them informed about the limitations of those choices, and then you do your best to mitigate any consequences or implications thereof. And then I will end with one very quick note. As you've said, you know, we've emphasised the ladies here and the woman viewing this, but it is as important to the men and I will give you a very quick example. How many men are going through that man no pause period. I'm 48. I can tell you a thing or two about that. But how many men have come to me having felt that they were declining in their muscle mass and declining in their performance in, you know, both in the bedroom and out of the bedroom and everything else? And they thought that testosterone was the magic fix. And what they did was they went and they were prescribed in good meaning testosterone, only to find that upon taking the testosterone, they were becoming more and more estrogenised. Right. Because remember, even when you take testosterone that same Cyp19a1, that same aromatase is going to convert some of that testosterone into estrogen. And men that Cyp19a1 gene comes in three different versions. A version that is going to convert your testosterone into estrogen, much faster, medium speed and slower. And so if you don't know which version of Cyp19a1 you have, you do not know what is your body's natural tendency to convert testosterone into estrogen, which can have so many implications on the choices you make, per going into hormone replacement. Lisa: Yes. And that's a thing that I'm discussing with my husband and my brothers at the moment, you know, like the implications of testosterone therapy. And it's not—it's a very simplified thing, ‘I'll just take testosterone, and I'll take a heck of a lot of it because I want more muscles’. It's not. And there are a lot of men doing that. And it works for some, and it doesn't work for others because of this very intricate knowledge that we need to have before we make these decisions. So Dr.Mansoor, I thin
A new technique for masking portions of raw genomic data increases shareability without sacrificing privacy. The post ‘Sanitizing’ functional genomics data may prevent privacy breaches appeared first on Spectrum | Autism Research News.
A new technique for masking portions of raw genomic data increases shareability without sacrificing privacy.
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What if we could understand the human cell in such detail that we could paint an accurate representation of a cell’s molecular organization? In this lecture, Dr. Manuel Leonetti outlines the different genome-wide approaches that scientists are using to build a complete map of the human cellular architecture. Understanding protein networks and localization could aid our quest to understand human biology and disease.
What if we could understand the human cell in such detail that we could paint an accurate representation of a cell's molecular organization? In this lecture, Dr. Manuel Leonetti outlines the different genome-wide approaches that scientists are using to build a complete map of the human cellular architecture. Understanding protein networks and localization could aid our quest to understand human biology and disease.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.08.288092v1?rss=1 Authors: Kwon, S. B., Ernst, J. Abstract: Identifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we take a novel approach and learn a score of evidence of conservation at the functional genomics level by integrating large-scale information in a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The computational method we developed to do this, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains a neural network, which is then used to generate a genome-wide score in human and mouse. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations even though it was not explicitly given such information. LECIF will be a resource for mouse model studies. Copy rights belong to original authors. Visit the link for more info
How Earth's Deadliest Creatures Mastered BiochemistryGuest: Christie Wilcox, author of "Venomous: How Earth's Deadliest Creatures Mastered Biochemistry"Snakes, spiders, wasps, and scorpions seem like the stuff of nightmares. Their venomous stings and bites are enough to make us stay far away. But where does this fear come from? And how does venom work anyway? Turns out, we may owe more to these fearsome creatures than we think. An Antidote to One of the Deadliest Venoms on EarthGuest: Greg Neely, Associate Professor and Head, The Dr. John and Anne Chong Lab for Functional Genomics, University of SydneyHorror movies centered on the great white shark are missing out on the ocean's real terror: the Australian box jellyfish. Ten-foot-long carnivores with 24 eyes and about 60 tentacles each, the box jellyfish is also one of the most venomous animals on the planet. Luckily, researchers from the University of Sydney are using CRISPR to close in on an antidote. Milking SnakesGuest: Carl Barden, owner and director, Medtoxin Venom Laboratories and The Reptile Discovery CenterTalk about hazard pay! This guy's job is to milk venomous snakes. Be grateful, since he's in the business of saving human lives.
Part 3: Dr. Jill Interviews Bob Miller of Tree of Life Health on How Overstimulation of NOX (NADPH Oxidase) from Environmental Toxins is Making you Sick!
LIVE now with Bob Miller with Tree of Life Health on Why NAD+ and NADPH are Critical for Your Long Term Health: How Overstimulation of NOX (NADPH Oxidase) From Environmental Toxins May be Making You Sick.
Dr. Jill Carnahan Interviews Dr. Bob Miller on Functional genomics and Perioxynitrite pathways and NADPH Steal
Volume 25 Issue 6, July 2020Podcast Editor Rob Howes discusses the SLAS Discovery 2020 July Special Issue with Guest Editors Davide Gianni and Stuart Farrow.This Special Issue of SLAS Discovery presents the topic “Functional Genomics for Target Identification” and is focused on three strategic pillars that form the foundation of the functional genomics discipline. Articles span a variety of relevant topics, from the development of more translatable models of diseases to the creation of validated screening libraries, technologies and computational pipelines to perturb gene function and enable quantitative interpretation of screening outputs.
Table of contents below. Professor Magda BOU DAGHER KHARRAT is a Plant Geneticist. She is head of laboratory Biodiversity and Functional Genomics at the Faculty of Science in Saint-Joseph University (USJ) Beirut. Adapting to the lockdown and working from home: 00:02:00 Research and conservation fieldwork (irises season): 00:03:50 A faulty anthropocentric perspective? 00:11:00 How do you decide which plants to conserve? (invasive vs native species, botanical gardens, cost of maintenance) 00:13:00 Jouzour Loubnan NGO (theory vs practice): 00:22:35 Awareness campaigns about flora, conservation practices, field trips, and hands-on activities: 00:26:00 Being passionate about what you're interested in, choosing to work in plant biology and conservation: 00:32:00 Has the effort been worth it? 00:38:20 Lebanon flora database (info + pics): 00:43:15 Ecosystems need to be protected because they are difficult to restore; how system restoration is carried out; adopting pioneer methods by studying animal excrements; hyenas are not only carnivores, they become herbivores based on the season: 00:47:00 International plant database initiative: 00:55:40 Cost of lab sample analyses is expensive in Lebanon: 00:57:25 Is there awareness about the importance of environmental conservation? 01:00:00 To restore and conserve or to cultivate? (agroforestry) 01:03:00 Arsal project: 01:06:30 Plant names: 01:11:00 Traditional vs innovative strategies: 01:13:20 A reflection on COVID-19 and the human place nature; maintaining the ecosystem balance: 01:20:40 Magda was selected as part of the faces of exchange, which highlights 80 years of the US Visitor Leadership Program: 01:33:00 Relevant links: Twitter: https://twitter.com/magdaboudagher Jouzour Loubnan twitter: https://twitter.com/jouzourloubnan Websites: http://www.lebanon-flora.org/ http://biodiversite-liban.blogs.usj.edu.lb/ https://www.researchgate.net/profile/Magda_Bou_dagher_kharrat Support the channel: Ko-Fi: https://ko-fi.com/decafquest Patreon: https://www.patreon.com/decafquest Twitter: https://twitter.com/Decafquest
Dr. Mansoor Mohammed is the President and COO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing and consulting and an industry first: Individually customized supplements. On today's show, we will discuss Testing Female Hormones.
Dr. Mansoor Mohammed is the President and COO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing and consulting and an industry first: Individually customized supplements. On today's show, we will discuss Testing Female Hormones.
We were SO lucky to be able to interview the brilliant Dr. Mansoor on this episode! Dr. Mansoor is one of the worlds leading geneticists and focuses on functional genomics - or rather, how our genetic profile dictates our overall picture of health. In this episode, Dr. Mansoor teaches us about why it is crucial to understand our genetics, and why it’s so important to have your genes read by someone versed in their function on a holistic level. We also touch on how important genes are for hormonal balance, especially in women!To order your own hormone genetic profile, and receive a FREE 30 minute consultation, click here and use clinician code YT220.
Giovanni TONON Director, Center for Translational Genomics and Bioinformatics, Head, Functional Genomics of Cancer Unit, Division of Experimental Oncology, San Raffaele Scientific Institute,Milan, ITALY in collaboration with Dejan LAZAREVIC Center for Translational Genomics and BioInformatics, Dibit2-Basilica, 3A3 Milan, ITALY speaks on "From targeted therapies to cancer evolution: a new paradigm to tackle cancer resistance". This seminar has been recorded by ICGEB Trieste.
Drug discovery is increasingly informed by genomics, which can significantly boost the chances of a novel therapy successfully navigating the lengthy journey from bench to bedside. But despite the rapid proliferation of genomic information, we still have a limited understanding of how specific genes and genetic variations drive tumour growth and therapeutic resistance. In turn, this limits our ability to identify and validate novel targets that are truly informed by biology and make an impact on disease progression – arguably the most crucial step in the whole drug discovery pathway. By Dr Menelas Pangalos & Steve Rees et al. If you'd like to view the original article then follow the link below: https://www.ddw-online.com/therapeutics/p322917-from-genotype-to-phenotype:-leveraging-functional-genomics-in-oncology.html You can also download the original article pdf here: https://www.ddw-online.com/media/32/136063/(3)-from-genotype-to-phenotype.pdf For more information on Drug Discovery World, head to: https://www.ddw-online.com
In this episode we speak with Dr. Mansoor Mohammed about the growing awareness & concern about hormone replacement therapy. Dr. Mansoor is the President and COO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing and consulting and an industry first: Individually customized supplements. He is widely regarded as a pioneer in medical genomics and has been the recipient of multiple academic and industry awards. He is the holder of several patents in the general fields of molecular diagnostics and genomics research and is one of the most sought-after national and international conference speakers in the genre of personalized medicine. Prior to his role at The DNA Company, Dr. Mansoor was: • Founder and President of ManaGene (2010-2018) • CEO of Combimatrix (Nasdaq traded leader in diagnostic genomic microarrays) (2006-2010) • Director of Genomics at Quest Diagnostics (The world’s largest reference laboratory with a market capitalization of over $10 billion US) (2003-2006) • Director of Research and Development at Spectral Genomics (one of the industry’s first commercial genomic microarray developers spun out of Baylor College of Medicine under Dr. Mansoor’s scientific leadership) Dr. Mansoor maintains an active clinical practice as a genomics consultant to some of the leading executive health clinics in Canada and abroad. Learning Points: • Pollution & baldness • What is the most recent research telling us about Hormone Replacement Therapy? • Is there a place for Hormone Replacement Therapy in women’s health? • How can women improve breast health? Social Media: www.thednacompany.com
In this Episode of the Epigenetics Podcast our guest Lucy Stead from the University of Leeds provides insight into her work on intratumor heterogeneity in Glioblastoma. In order to tackle this area she uses an holistic approach including Computational Genomics, In silico Modeling and Functional Genomics in order to test whether treatment-resistant subclones emerge in recurrent tumors, and characterize them in clinically relevant ways in multiple patients. And this is just a glimpse of what is discussed in this Episode. References Lucy F. Stead, Helene Thygesen, … Pamela Rabbitts (2015) Using common variants to indicate cancer genes (International Journal of Cancer) DOI: 10.1002/ijc.28951 Caroline Conway, Jennifer L. Graham, … Lucy F. Stead (2015) Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq (Oncotarget) DOI: 10.18632/oncotarget.5529 Alastair Droop, Alexander Bruns, … Lucy F. Stead (2018) How to analyse the spatiotemporal tumour samples needed to investigate cancer evolution: A case study using paired primary and recurrent glioblastoma (International Journal of Cancer) DOI: 10.1002/ijc.31184 Georgette Tanner, David R. Westhead, … Lucy F. Stead (2019) Simulation of heterogeneous tumour genomes with HeteroGenesis and in silico whole exome sequencing (Bioinformatics (Oxford, England)) DOI: 10.1093/bioinformatics/bty1063 Nora Rippaus, Alexander F-Bruns, … Lucy F. Stead (2019) JARID2 facilitates transcriptional reprogramming in glioblastoma in response to standard treatment (bioRxiv) DOI: 10.1101/649400 Contact https://twitter.com/activemotif https://twitter.com/epigenetics_pod https://www.linkedin.com/company-beta/35651/ https://www.facebook.com/ActiveMotifInc/ eMail: podcast@activemotif.com
Functional genomics is super exciting to me and is an exploding field. It sets the stage for each person's biochemistry and helps me to understand why a certain supplement or treatment works perfectly to heal one person's body and yet the same supplement or treatment doesn't work for another.
The Awakened Man: A Repository For Holistic Health, Red Pill Alpha Masculinity, & Ultimate Freedom
Functional genomics time! In this episode of Holistic Health News, Gregory interviews Heather Rae on functional genomics. Later she shares why she… The post #212: Functional Genomics & Vaccine Awareness with Heather Rae appeared first on Naturopathic Earth.
I'm constantly blown away by the amount of genetic data and actionable information one can garner from a simple bit of saliva. In today's episode, you're going to get an insider glimpse into how to go way beyond something as simple as 23AndMe or Ancestry and instead learn how to get truly useful health information that you can use to enhance health, performance, sleep, gut function, neurotransmitters and cognition and much more. My guest on this podcast, , has an extremely impressive background in the field of genetics. His credentials include: -BSc. Specialized Honours in Molecular Genetics | University of Guelph | Guelph -Doctor of Philosophy with Distinction in Molecular Genetics & Immunology | University of Guelph | Guelph -Postdoctoral Clinical Cytogenetics Fellowship | University of California | Los Angeles -Postdoctoral Clinical Cytogenetics Fellowship | Baylor College of Medicine | Houston Dr. Mansoor is now the President and CSO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing and consulting and an industry first: individually customized supplements based on your genetics. He is widely regarded as a pioneer in medical genomics and has been the recipient of multiple academic and industry awards. He is the holder of several patents in the general fields of molecular diagnostics and genomics research and is one of the most sought-after national and international conference speakers in the genre of personalized medicine. Prior to his role at , Dr. Mansoor was: - Founder and President of ManaGene (2010-2018) - CEO of Combimatrix (Nasdaq traded leader in diagnostic genomic microarrays) (2006-2010) - Director of Genomics at Quest Diagnostics (The world’s largest reference laboratory with a market capitalization of over $10 billion US) (2003-2006) - Director of Research and Development at Spectral Genomics (one of the industry’s first commercial genomic microarray developers spun out of Baylor College of Medicine under Dr. Mansoor’s scientific leadership) Dr. Mansoor maintains an active clinical practice as a genomics consultant to some of the leading executive health clinics in Canada and abroad. During our discussion, you'll discover: -What makes each DNA test different and how to choose what's right for you...9:30 Consider the various elements of genetic testing: SNPs (pronounce "snips"; single nucleotide polymorphisms) Copy number variation (CNV) INDEL (insertion/deletion polymorphism) Understand how the various labs go about testing the elements Humans have two identical copies of the DNA code (from each parent) When testing for SNPs, the genetic paragraph is "read" and looks for variations between the two The more paragraphs you try to query simultaneously, the greater risk of error (false negatives/positives) Characteristics of a proper DNA test: Concern is for the physical manifestation of the genes, not the genes themselves Cellular function is key indicator Identify the genes that influence the desired outcome Pinpoint the specific DNA to test vs. "shotgun" approach Avoid drawing data for data's sake -A review of Ben's DNA test and how they compare to his two sons...25:00 Two different reports: Genome Pulse Report and Hormone Pulse Report (looking at the GPR) Vascular function Cells that line the vascular system receive the most wear and tear 9P21 markers (not genes) are correlated with the lining of the blood vessels; "the heart of the human genome" A alleles and G alleles The more G alleles you have, the less resilient is the endothelial lining Increase good quality vegetable matter People with multiple G alleles benefit less from vegetable matter (like red wine) than those with none Smokers are more likely to die of vascular disease than lung disease Glutathione S-Transferase (GST) pathway is one of the key pathways in the body Glutathionization: the cellular process that neutralizes toxins in the body What happens when someone doesn't have 2 copies of a gene... You sometimes have genes you didn't inherit from either parent Talking about SNPs in the gene is irrelevant; As is epigenetics (alter the expression of the genes, not the genes itself) 3 vitally important GST genes: Theta 1, Pai 1, Nu1 Should a person only have 1 copy of a gene, they will produce 50% less than someone with 2 copies Ben Greenfield has 1 copy of the GSTT1 gene (as does 60% of the population) Important to not exceed a healthy toxicity threshold Ben Greenfield does not have the GSTM1 gene at all Useless to discuss SNPs for that gene The M1 gene is a backup: it can be lost with less consequence than other genes (such as the T1) What this means is that Ben Greenfield has low to average glutathione detox capacity Must be more cognizant of diet, environment, etc. Ben's two boys are missing the GSTT1 gene completely -Personalizing diet and/or supplements based on DNA test results...57:25 Youtrients [link] Nothing compares to an optimal diet (eating whole foods) Customized based on dietary limitations (lactose intolerance) Ethnic and geographic factors, as well as the environment during weaning, affect how to interpret test results Elites of Victorian era England adjusted their lifestyle (living in Scottish highlands in the autumn months) Reduce, not promote, supplementation, to where only necessary Our bodies are not designed to accommodate many of the supplements on the market "Is there a cellular function that is dysfunctional?" Then address that through supplementation More is not always better when it comes to genetics 3 disparate aspects of cellular function: Endothelial quality Detox capacity Insulin productivity and function in response to diet -Differences between the hormone pulse report and the genome pulse report...1:18:25 BDNF (brain-derived neurotropic factor) is one of the most important genes in our body First thing looking at: How does the body (male or female) convert progesterones into androgens, into estrogens t-intersection (4 points): How efficiently converting progesterone into androgens 3 things happen when you make testosterone: Use it Convert some of it into DHT Metabolize (glucuronidation) Ben has the perfect balance of the t-intersection Ben's boys are identical, except have a higher predisposed conversion of testosterone into estrogen -About the ACTN3 gene and its relation to exercise types...1:28:50 -And much more... Resources from this episode: - Click here for testing with Youtrients through the TheDNACompany. They offer their complete functional genomics test package for $399 USD (that’s a savings of $50 from retail price), and your test package includes both Hormone and Genome Pulse panel tests as well as a clinical report for each panel, along with full access to their webinar series, which introduces the science and interpretation of your genomic results with regards to key biological systems and processes. - Ben's Hormone Pulse results from TheDNA Company [pdf-embedder url="/wp-content/uploads/2019/06/Ben-Greenfield-HORMONE-PULSE-REPORT.pdf" title="Ben Greenfield HORMONE PULSE REPORT"] - Ben's Genome Pulse results from TheDNA Company [pdf-embedder url="/wp-content/uploads/2019/06/Ben-Greenfield-GENOME-PULSE-REPORT.pdf" title="Ben Greenfield GENOME PULSE REPORT"] Episode sponsors: -: My personal playground for new supplement formulations. Ben Greenfield Fitness listeners receive a 10% discount off your entire order when you use discount code: BGF10. -: Contains a host of anti-inflammatory, anti-obesity, and anti-allergy benefits. For this reason, I have decided to now make consumption of hydrogen-rich water an important part of my daily nutritional routine...and I highly recommend it! Enter code: BEN at checkout and get 30% off your order! -: Halo Sport revolutionized physical training by being the first-ever product that can increase your neuroplasticity by putting your brain into a state that neuroscientists called hyperlearning. The fully upgraded Halo Sport 2 was just announced and it’s pre-selling for just $279 (less than half the price of the first model) when you use code: GREENFIELD. -: Quality is our Gimmick isn’t just our slogan, it’s a commitment we honor with every stitch we sew. 100% money back guarantee. Get 10% off your order, PLUS free shipping on any order over $99 when you use discount code: BENG. Do you have questions, thoughts or feedback for Dr. Mansoor or me? Leave your comments below and one of us will reply!
Benedict Cross, Head of Functional Genomic Screening at Horizon Discovery, joins us this time. Join us as we discuss, among many other things: ❇ Functional Genomics and the impact of CRISPR on drug discovery ❇ Why knowing what NOT to do can be the most important thing you learn ❇ How the outcry over GMO kick-started Benedict's career in science ❇ Using your network
If we have learned anything from scientific research in the last 20 years, it is that finding cures to complex diseases is difficult. Despite the promise of the genomic revolution, disease progression and patient outcomes are still not easily predicted by genetic factors alone. Part of the explanation for this gap is that agerelated diseases are heavily influenced by changes in cellular metabolism. For example, cancer, the quintessential genetic disease, is being redefined by metabolic abnormalities, endowing tumours with the ability to outcompete normal cells in the tumour microenvironment. Adding fuel to the fire, there is early evidence that directing the metabolic programming of immune cells may improve the efficacy and durability of immunotherapies that are completely agnostic to cancer’s genetic drivers. Measuring metabolism, either functionally or using metabolomics, provides insight into the dynamics of cellular energetics. Original article by Dr David Ferrick If you'd like to view the original article then follow the link below: https://www.ddw-online.com/enabling-technologies/p315008-metabolomics-a-playbook-for-functional-genomics.html You can also download the original article pdf here: https://www.ddw-online.com/media/32/113374/metabolomics-a-playbook-for-functional-genomics.pdf For more information on Drug Discovery World, head to: https://www.ddw-online.com
In this episode we speak with Dr. Mansoor Mohammad, President and COO of The DNA Company, a leading and innovative provider of comprehensive Functional Genomics testing and consulting and an industry first: Individually customized supplements. In this fascinating conversation we discuss many topics including: • What Functional Genomics is • What role genetic testing can play in our health • If all Genomic testings are created equal • Misconceptions surrounding the BRCA gene https://www.thednacompany.com/
Transcript of the February Podcast, “Getting Personal: Omics of the Heart”, Episode 13 Hosted by Jane Ferguson Assistant Professor at Vanderbilt University Medical Center & Associate Editor of the Circulation: Precision and Genomic Medicine journal of the American Heart Association Jane Ferguson: Hello. This is episode 13 of Getting Personal: Omics of the Heart. It's February 2018. I'm Jane Ferguson, an assistant professor at Vanderbilt University Medical Center, an associate editor at Circulation: Precision and Genomic Medicine, and an occasional podcast host. This month, I talked to Kiran Musunuru and Svati Shah about how they spearheaded name changes for Circulation Cardiovascular Genetics and for the AHA Council on Functional Genomics and Translational Biology, and Andrew Landstrom talked to Kaytlyn Gerbin and Brock Roberts from the Allen Institute about some extremely cool work they are doing with CRISPR and IPS cells to create fluorescently tagged maps of live cells, which allowed them to image and better understand the structure and function of individual cells. I'm delighted to have two guests on the podcast today, Dr. Svati Shah is the current chair of the AHA Council on Genomic and Precision Medicine formerly called the Council on Functional Genomics and Translational Biology. She is an associate professor of medicine at Duke University Medical Center. Dr. Kiran Musunuru is editor in chief of Circulation Genomic and Precision Medicine formerly named Circulation Cardiovascular Genetics, and he's an associate professor of medicine at the University of Pennsylvania Perleman School of Medicine. Dr. Shah and Dr. Musunuru were kind enough to take time out of their busy schedules to join me for a joint discussion on the recent enhancement of name changes for our council and our journal. With tight schedules and last-minute flight cancellations we didn't have ideal settings for recording, so apologies in advance for a little more background than usual. My instruction highlighted a number of name changes and astute listeners will have noticed that the new names for both the journal and the council are very nicely aligned, so I know this was not a coincidence, and I'd love to hear from both of you, what prompted the decision to change the respective names of the council and the journal, and how did you come together to streamline these name changes? Svati Shah: Well, maybe I'll take a first start, you know, we, we're really lucky in our council, we have a very, you know, certainly one of the smaller councils [inaudible 00:02:26] we have a very collegial spirit that wants to get things done. So, these conversations actually started probably three years ago, umm, when Jen Howell was chair of the FGTB council. And we realized that not only was our constituency broadening in expertise and breadth and depth, but also, umm, the desire to kind of move beyond the really wonderful work the council is doing around technology platform, genomics, genetics and you know important advances in many of our council members have made in the translational biology field and really thinking about the fact that we have this amazing expertise that can come together across a wealth of disciplines to really translate what's being done in the omic space, and apply it in this new world of precision medicine. And so, umm, that is what stirred really thinking about a name change so that not only would it reflect this expanding constituency in expertise and hopefully draw even more people, across the, you know, wide expertise. But also to harmonize more with people who are in other councils, including clinical cardiology, and people that, really, in the end we are actually quite allied with scientifically, but perhaps those councils didn't recognize really what our council was about because of our previous name. So in that context, you know, it's been wonderful. Kiran has been a wonderful partner in all of this, he's been a real leader in the council and over the past two years we have had many conversations across council leadership and the entire council, and thinking about what this name change would be. And actually, it was almost a consensus amongst council leadership to choose Genomic and Precision Medicine as the name, really to reflect our core beliefs and our core science in genetics and genomics, but also to reflect the expanding expertise of all the different omics platforms, our expertise in clinical genetics with more genetic counselors joining our council, and our expanding expertise in computational biology. And this really allied nicely also with the American Heart Association building a very important institute, the Precision Medicine Cardiovascular Institute. So, I'll let Kiran go from here but again, Kiran has really been a great partner in this and he can kind of expand on that story and how that led to the journal name change. Kiran Musunuru: Sure, so, with respect to the journal, I think these changes have been growing for a while. I think a lot of the same considerations came into play, the feeling that the journal with the name Circulation Cardiovascular Genetics was perhaps too narrowly defined given how the field, how the science was evolving. And the other consideration is that the Functional Genomics and Translational Biology Council has had a journal, a companion journal if you will, all of this time with a fairly distinct name, Circulation Cardiovascular Genetics, and so it wasn't necessarily obvious to those who are not on the inside so to speak that there was supposed to be a very tight connection between council and journal, that the journal really was the journal of the council and so in the process about deliberating about a council name change, it became natural to think that, "Wow, wouldn't it be nice if the journal could execute a similar name change", and separately, even though this predates my tenure as editor of the journal there had been conversations going on separately or independently that perhaps the journal would benefit from signaling that it was not just about cardiovascular genetics in the very narrow sense, but was really about a much larger area of science. And so there had already been contemplation for quite a while about a name change and so when I assumed the editorship I didn't really have to do much to convince anyone that this would be a useful thing. The scientific publishing committee of the American Heart Association and all the various people involved publishing the journal were already sort of primed for a name change and then it just ended up being a nice convergence of opportunities, Svati with her work in the council and really showing the leadership to lead the transition from Functional Genomics and Transitional Biology to Genomic and Precision Medicine. That really laid the groundwork, and because it was such a deliberative process, such an inclusive process, involving dozens of people on the leadership committee of the council as well as general membership of the council, it was really a no-brainer. The hard part had already been done, the thinking had already been done and I was straightforward to say that we should change the name of the journal to match, Circulation Genomic and Precision Medicine. Jane Ferguson: Have there been any logistical difficulties in getting this name change through, or has it all happened very organically? Svati Shah: The American Heart Association has been a real partner in the name change, sometimes things require many layers of approval and in fact, it has been a relatively seamless process. We came up with a consensus around the name change and later applied formally for that change in the council name, and that was pretty quickly approved by the Scientific Advisory Committee, within a few months really. Our name change became official and we are in the exciting time now of advertising and kind of marketing the name change and appeal to a broader constituency and really reach out to group that perhaps wouldn't have realized that this council is a great home for them again thinking of genetic counselors and computational biologists. So, it really, you know, has been a surprisingly seamless and fun process. Kiran Musunuru: As I mentioned before it was already kind of in the air that a change was imminent and so when I posed the name change to the Circulation Genomic and Precision Medicine it ended up being a very smooth transition. It was timed so that the volume change, that is changing from the volume associated with the calendar year 2017 to the volume associated with the calendar year 2018, January first ended up being a very logical transition time and so that's when the change occurred. And happily, the council name change ended up occurring almost in lockstep; whereas, you know within a few weeks of the journal announcing its name change the council was able to announce its name change as well. I think that has had a reinforcing effect across the American Heart Association and its membership. It really signals that the council and the journal are tightly tied together, are partners in moving in lockstep. Jane Ferguson: Svati, this question's probably more for you, so what does the name change mean specifically for existing FGTB council members, and what if anything will change, and then what might it mean for potential new members who are trying to decide what council to join? Svati Shah: That's a great question, Jane, you know I am a pragmatic person and I think our council also reflects that pragmatism. We get a lot of things done and we, I think, spiritually all agree that we shouldn't just change the name just for the sake of changing the name. And so we really, actually the name change followed [inaudible 00:10:18] were involved in, these discussions are a year and a half of really thinking about what direction we wanted the council to go and then what the sort of short and long term goals of our council are and then how does the name change effect the long term goals. So, we have a lot of great initiatives in the short and long term, which again will capitalize on our broadening expertise in these different clinical genetics and precision medicine and really, translating genomic and omic findings into, into important patient care. And so, we have several things coming down the pipe that are sort of proof of principle examples of what the name change reflects. So, one example is that we are now working on developing a certificate in medical genomics with the idea that we really need more genetics education. Our council has been very much embedded in genetics and genomics education, Kiran being a key example of that. And now we are expanding that into thinking about how genomics is applied to clinical medicine but making it at the level that is digestible and understandable and is easily applied by a general cardiologist and even primary care doctors will be able to use that resource. And the idea is this will be your self-sustaining certificate that's given through the American Heart Association, so we have a group that's been working on that certificate and hopefully that will be coming out soon. Another key component of what we're doing is trying to reach out more and partnering with other associations including the American College of Medical Genetics and the National Society of Genetic Counselors, again really thinking about how we transition our important scientific discovery work into translation implementation science around patient care. To give you some examples of what that means in terms of what the name change is reflecting, I think with the right use, for the second part of your question, which I think is a really important part of your question is, we want to attract more people in the computational biology field, in the precision medicine space, in the clinical genetic space and again reaching out to genetic counselors through some of these societies, because we, just the wave of precision medicine is here, is going to expand even more and the expertise within our council that was already there but that now we can expand. I think it will be leveraged to really make important contributions to making sure that those efforts in precision medicine are done well, or done responsibly and are done with the patient in mind because in the end the American Heart Association is at the forefront of patient advocacy group. This is a really exciting time, I think that, you know, however you want to define precision medicine the bottom line is precision medicine is here and we can't have, it's not going to be a single faction of individuals or a single expertise that is really, is going to be able to leverage fundamental scientific discoveries whether its genetics, genomics, metabolomics, proteomics, and really translate them responsibly into patient care, so it's going to involve an interdisciplinary and multi-disciplinary effort. I feel really proud that I'm part of the AHA and that we sort of have this perfect storm between Kiran's leadership in the journal, our council changing, you know, its goals and its name aligning with the Institute for Precision Cardiovascular Medicine within the AHA. And I think that, you know, it's not all rainbows and sunshine. We have a lot of work that is cut out for us in the next few years to figure out ways that we can tangibly and concretely, and again responsibly, work together across each of these three components of this perfect storm to make sure that it’s not just a glitzy name change and that there is actually substance and behind all of it, so, you know, it will be, there will be challenges, there will be obstacles, but I think that the amazing people within each of those three components, I feel very confident that we are going to be able to do it well. Jane Ferguson: Yeah, I agree, as a member of the council, if anybody can do it I think this group of people can do it, so it's very exciting to see, so thank you both for joining, and congratulations again on the new names. It's really exciting to see these, you know, new directions for the council and the journal working together. And I really look forward to seeing all the great initiative that will be coming out in the next few years. Svati Shah: Thank you, Jane. Kiran Musunuru: Thank you, Jane. Andrew Landstrom: My name is Andrew Landstrom, and I'm an assistant professor in the department of pediatrics section of cardiology at Baylor College of Medicine. I'm a member of the early career committee of the American Heart Association Council on Genomic and Precision Medicine, previously the Council on Functional Genomics and Translational Biology, and I'm joined today by Brock Roberts and Kaytlyn Gerbin, who are scientists on the stem cell and gene editing team at the Allen Institute. Here to discuss a little bit more about CRISPR editing and what they have done for live cell imaging using fluorescent proteins. So, Brock and Kaytlyn, I'm hoping you can discuss a little bit about what the Allen Institute is and your overall research mission and goals. Kaytlyn Gerbin: Yeah, great, so this is Kaytlyn and thanks Andrew for having us on, and we're really excited to share a little bit of the information about what the institute is doing, because we're building a bunch of tools that we think would be really useful for the research community. So, we're excited to get the word out there. And so, the Allen Institute is a non-profit research institute, and we're based in Seattle, Washington, and, essentially what we're trying to do is better understand the cell. We want to understand the various states the cell can take based on structural organization of how different organelles work together. And so, we're doing this, essentially by live cell imaging and also combining that with predictive modeling so that we can build tools to be able to understand structure-function relationships and how cells behave in a healthy state or in a diseased state. So, you can kind of think of this as, we like to say sometimes like a Google Earth for the cell, so if you kind of think about it in that context, a lot of times, you know you could look at the cell at a really high level just like you could look at the Earth at a very high level. Then you could zoom in further and you could look at an individual pathway maybe that you're interested, or perhaps, as an analogy, like a different highway within a part of a city. But you don't really understand how all that works together and how the city functions together until you start to put in things with spatial organization, or maybe temporal dynamics, or how different parts of the structures, or different structures and organelles work together to form the unit that is the cell. And so, essentially, we're trying to generate a bunch of data so that we can build predictive models to help us understand that better. And, we're doing this with human induced pluripotent stem cells, and the first cell state or cell type that we're studying is cardiomyocytes after differentiation. And so, yeah, as we're kind of generating this data we are a non-profit institute, and all of our lines and our plasmids, protocols, data, pretty much everything that we make is becoming publicly available as it passes QC. And so, yeah, we're excited about that, I don't know if, Brock, you have anything else to add. Brock Roberts: Yeah, just I think an important concept that we're often working with is scale. And, biology exists at certain scales, and that's certainly true for cells and the Google Earth analogy holds. You know, at some level if we want to understand the cell at the scale of its entirety, but we have to kind of cut that down and understand cells at the level of its parts. And, they're working together as we know, and can infer, but we try to find a way to look at the part one by one and then put it all together in a model that's predictive. And the predictive part is going to be really important. Much like Google Earth can allow us to, you know, look at a traffic pattern in the city or something like that once the data is filled in. We hope to fill in enough data by looking at the cells constitutive parts to make the predictive model. Andrew Landstrom: And not only looking at, sort of, constitutive parts, you're doing this in a physiologic live cell, so really it's Google Earth, but it's Google Earth in real time as cars are driving down the freeway and people are walking down the street. Brock Roberts: Right- Kaytlyn Gerbin: Yeah, exactly. Brock Roberts: Yeah, that, that's where the dynamics of the cell can really come to life if you've prioritized looking at live cells, which are obviously incredibly dynamic. Andrew Landstrom: And so, you know to be able to accomplish this, you all have come up with some pretty novel methods. Would you talk a little bit more about your CISPR editing approach, and how you've applied this to different lines and to get, sort of, different markers into cells? Brock Roberts: Right, sure, the, we should say that we owe a lot to the development of CRISPR-Cas9 editing, which preceded us by a few years, but we've tried to kind of scale it up in some important ways. And, really the important thing to appreciate about this process is it's a way to make a very precise, precisely guided DNA break in the genome of a cell. And we do this in human induced pluripotent stem cells, and so we can quite precisely choose a position or location in the human genome and trigger DNA damage, trigger breaks in the DNA molecules that make up the chromosomes. And we can do this with, kind of a highly specifically guided RNA molecule that we complex with this Cas9 nucleus molecule, and these are, very famous molecules now, over the last few years they've become very well known. And the upshot of this is we can, sort of trick the cell into repairing that DNA break using the processes that are always at play in living cells to resolve breaks in DNA, but we can sort of trick that process to add something additional at a specific site. And the additional sequence that we use is a tag sequence that corresponds to a fluorescent protein after the DNA is expressed and translated. And so, what we can effectively do is tag proteins that are produced in a highly endogenous, natural fashion within cells. And the proteins that we can tag in this way, using this method, correspond to some of the most canonically recognized structures and organelles within the cell. And so, at this level we try to choose proteins, tag them in this manner, and take advantage of the fact that they will localize predictably to some of the dozens or hundreds of structures that make up cells. Kaytlyn Gerbin: Yeah, and a key thing I think to add that Brock kind of mentioned was that this isn't any over expression, we're doing all this endogenously. So it’s really like, pretty, I think that's a big advancement over what has typically been done in the past with a lot of fluorescent tagging of proteins within the cell. Brock Roberts: Right, but what's important to appreciate is that we're using the cells endogenous copies of each protein, expressed from the genome. We've done it in about 30 different genes so far. And we have a high success rate in accomplishing this process, all the way through to completion, which is to say that we know that we can introduce a tag onto at least one copy of each gene that is, that encodes a protein that can be tagged this way, and then we can monitor the cells over several months and ensure that this doesn't have a negative consequence on their growth or on their ability to differentiate or something like that. Our quality control process. We have a high success rate so far. Andrew Landstrom: And that's really, in my eyes, one of the key, key sort of, innovative factors of your work, in that these are endogenous proteins that are able to be expressed and then to be imaged in real time without really disrupting the underlying cellular physiology. Kaytlyn Gerbin: Yeah, and we do care a lot about what you just said, that it doesn't have any negative effect on cell behavior because we are using these as a surrogate for understanding cell behavior in, hopefully, a normal context. And we do an extensive amount of quality control work and all of that QC data is available on our website, and then you can actually access all of our cells through Coriell and all of the QC data for all those cell lines is made available, and we've also done a pretty extensive job outlining the QC that goes into this process so that, hopefully, people will take a look at that when they look at our cells and understand what we've done, but we also hope that this will kind of help set a standard for things that other people should be looking at when they're doing editing on their own. Brock Roberts: And we really hope that people take these cells and do experiments that we don't have the bandwidth to do, and test them in ever expanding ways and let us know and report on it. Let us know how the cells perform and their unique assets. Andrew Landstrom: Yeah, and I think all that sort of transparency with the quality control really makes it user accessible and just sort of invites that degree of collaboration, that's great. Kaytlyn Gerbin: Yeah. Brock Roberts: Yeah, we hope so. Yeah, we think so, too. Andrew Landstrom: So how many cell lines do you have available? Kaytlyn Gerbin: Yeah, so, currently, and again you can access all these lines on the website, but we have 16 lines that are released that have gone through the full QC process. Those are available now, and we have another six that are listed as in progress, which means that they will be released very soon. Just to give you a few examples, so again, we're tagging proteins to label organelles in the cells. So, a lot of times, you know there's a lot of different kinds of proteins you could use to tag an organelle, so we've chosen a subset of those. So, we've tagged, for example, Tom20 to label mitochondria, Lamin-B1 for the nuclear envelope, alpha tubulin to look at micro tubules, and we also have started doing a lot more endosomal trafficking pathways, so like the endosome, lysosome, peroxisome, for example, and then a few other epithelial markers such as tight junctions, desmosomes, and actin. And so, there's a kind of a bunch of structures. Those are just some examples of what we've been starting with tagging, but one of the reasons why we chose to use induced pluripotent stem cells for this whole model is because they do have the ability to differentiate into many cell types. And, I mentioned earlier that we chose to start with cardiomyocytes as a key cell type to look at, and so all of our cell line, as part of the QC process go through a cardiomyocyte differentiation protocol. And that kind of helps us ensure that the cells are pluripotent and that they can become a defined cell type and that the structure that we've labeled still is present in that differentiated cell. But it also means that we can start looking at some really interesting things in terms of how these structures change during differentiation and change from the stem cell state to the cardiomyocyte state. And so, one thing that we really started doing towards the end of last year, and we have lines coming out, hopefully soon on some cardiac specific tags. And so, to give you a few examples of things that we're working on, we have cardiac troponin I 1, and this I think will be available, I think it's passed QC and will be available pretty soon. And then we also have, we're working on sarcomeric alpha-actinin, titin, some gap junctions so that connexin 43, and then also starting to do a few signaling pathways and one that is of particular interest for the cardiomyocyte field would be beta-catenin for Wnt signaling. So, we are kind of expanding on that list as well. So, we're really excited to start looking at these cardiac structures in the cells. Brock Roberts: One way to summarize kind of, our strategy and one thing unites all of the different gene and protein targets that we have produced and focused on so far is to really think about the product gene or the protein as a reporter for an organelle or a structure in the cell. So, there are of course an extraordinary number of genes and proteins using this method, and there are many different justifications that would fly for why you would target a particular molecule, a particular gene, a protein of interest, but, what we really try to focus on are proteins that serve as a reporter for a structure. Andrew Landstrom: So, have you tagged any ion channels? Brock Roberts: We have several targeting experiments that are, that take advantage of tagging the transporter molecule. One that is available is a transporter in the mitochondria, a transporter to the outer membrane, Tom20. And we're also making connexin 43 available for gap junctions. These proteins that function as trans-membrane transporter molecules accommodate the approach quite well. Another that is a bit further behind, but we hope to make available before too long would be marker of the sarcoplasmic reticulum and cardiomyocytes. This is a serca protein. Andrew Landstrom: So, with all these cell lines at your disposal, you've spoken to, sort of, the dynamic changes that occur both in differentiation of cardiac myocytes and cellular development and cell physiology, what are some other thoughts that you have that these lines might be able to show us? What are some fields that might be immediately informed by these models? Kaytlyn Gerbin: I mean, I guess just kind of on a big pictures I think that having the ability to study live cells and look at different structures in the cell will help us better understand structure-function relationships. So I think that in cardiomyocytes that, you know, makes a lot of sense, but I think even just in the stem cell field, being able to understand how localization of a particular organelle corresponds to a different state that the cell might take. And so we kind of are thinking about a lot of these different stages and states that the cell can pass through and how do we characterize that based on just kind of at a healthy or just kind of quiescent state, and then comparing that to different protivations, so looking at disease or maybe change in time, change in mutations, drug response, response to stress and how are the structures changing and how does that kind of dynamic integration effect how the cell behaves as a whole? And I think that that's one thing that we're really trying to do at the institute that is out of the scope that a lot of federally funded academic labs can do. A lot of times people are focusing on specific pathways or a specific molecule or a specific protein and don't necessarily have the bandwidth to look at the cell on a systems level. And so, kind of as Brock mentioned, with doing these different proteins as tagging the organelles we're hoping that being able to integrate that and generate enough data where that starts to become predictive I think can be really, really powerful. So... Brock Roberts: Yeah, and there's another thing to add that's is kind of a larger thought that we are very preoccupied with and interested in, which is to take kind of a post genomic view of biology and cell biology in particular. Genomics has been so explosively successful in allowing us to document and document the state of cells at the level of which genes, which of the many, many, hundreds and thousands of genes are active in a particular cellular state, in a particular cell type or particular state that that cell's in. We can easily get lists of genes that we know are functioning and turned on. What we want to do is take that to the next level and start defining a cellular state as a combination, a particular combination of dynamic behavior of those molecules which we can actually see. So we want to be able to see the parts work together. Not just have a list of the parts, and define states in that way. Kaytlyn Gerbin: Yeah, and I think you kind of asked about what kinds of communities might find these tools useful and I think lot of the disease, we're thinking about how this might apply to disease modeling or drug screens or even developmental biology and kind of studying things like that, so I think a lot of our, we have some collaborations, and we've also been really trying to expand what kinds of groups and communities are using the cell lines. There's been a lot of, kind of positive feedback on people taking, you know, a highly defined cell type that has a lot of QC done, and then having the right tools to be able to start to look at things like that. So, I think we kind of mentioned some of the tools we have, but I just to kind of restate that, all of the cell lines that we listed, along with many more, are available at Coriell. And then, in addition to that you can get the plasmids that we've used, which have gone through also an extensive QC, so if people are working on patient derived, on their own patient derived IPS lines, you know, you could get the plasmids for whatever reporter and then put those in to your own cells. And we do have protocols available that describe our whole process in a lot of detail for how to do that and kind of different QC steps along the way. Brock Roberts: Yeah, we describe each targeting experiment in enough detail for it to be, we hope, recapitulated in any human cell line or cell type without too much strain on behalf of the person that's doing that work. So we hope to kind of inspire people to try this, even if they might not be familiar with it. Kaytlyn Gerbin: Yeah, and another thing is that our data is also available, so all of our imaging data that we're doing, and then, you can actually find that we have a website called the Allen Cell Explorer. And from there you can go through and look at all of the imaging, no, pretty much all of the images that have gone through our pipeline are now on the website. So you can go through and actually look at individual cells that were imaged during what, you know, as live cells, and then look at different structural tags that are in there. Another thing that you can see on that is the predictive modeling, and so what we're able to start doing is predict the structure of, let's say, mitochondria based on the nuclear shape and another organelle that's in there. So, we're able to start doing a lot of that. So that, I think, will be really useful to people. We going to add about the label free...? Brock Roberts: Yeah, and some of the more interesting results that have emerged recently are, are the ability to infer through machine learning approaches and neural network approaches the status and state and sub-cellular localization of certain organelles in the cell and structures in the cell that are actually unlabeled. Those can be inferred from the sort of sophisticated analysis of bright field, you know, images that are not displaying any particularly obvious properties, any tags or anything like that. But because the work has been done in the background to train these models and deep learning approaches with individual cell lines that do have these very specific reporters of distinct structures and organelles, because that data set exists, our modeling team and imaging team is able to appear actually quite deeply into the state of cells that are actually not labeled. Andrew Landstrom: Wow. Brock Roberts: So, it's pretty, pretty interesting. Kaytlyn Gerbin: Yeah. Yeah, we don't have that up on our website yet, but that's in the works to get that actual predictive model. So essentially what that would mean then is that you could take a bright field image in your own lab and then put it into this model, and then get information about maybe where the nucleus is or where the mitochondria are or where the actin is predicted to be. And all that is actually trained off of thousands and thousands of images that have come through the imaging and then the modeling pipeline. So, I think that that tool itself, once that is out and fully QCed I think could be, have a big impact right away. At least we're hoping that it will. Brock Roberts: Hoping. And those computational algorithms are among the publicly available tools that we have that can be found through our website, and our publications that are coming out. Andrew Landstrom: That's absolutely fascinating. Are you able to provide a specific example of how you've used, sort of, artificial intelligent, deep learning predictive modeling to infer a physiologic sale or response that was not directly observed? Brock Roberts: Well, I think the response is, we're really hoping to go in that direction. To use this to, I guess, if you will, take shortcuts toward a response in the form of a state change after we alter the environment in some way, or perhaps alter the genome to mimic a disease, mutation, or something like that. Right now, we are building the relationships. So, we can, we know, and I guess one example we can give is progress through the cell cycle. Kaytlyn Gerbin: Yep. Brock Roberts: That would be one kind of clear example that we, we haven't done a lot yet to manipulate the cellular environment or trigger cells to go through different states, but obviously cells that are in culture and proliferating alter their state by progressing through cell cycle. So that's one example that we can detect. We can clearly look at how the morphology of cells and different cell cycle states that emerge that are their chromosomes are compacted or dispersed as they undergo synthesis or undergo division, progress through metaphase and so forth. We can look at those cues and connect the state of the cell with respect to the cell cycle, to the state of some of the organelles, with the state of the mitochondria, for example. And we're hoping that same approach will hold up when we trigger, in some cases, more subtle changes to the physiology of cells. Andrew Landstrom: That's particularly fascinating. I think the, you know, the ability to leverage that in the setting of, like you were mentioning, patient derived IPSCs from heritable diseases. You know, these sort of monogenic disease models that impart a biophysical defect in the cell could then be modeled and not only directly observed, but perhaps indirect cellular physiology might be inferred in a way that we really haven't been able to do so previously. Brock Roberts: Absolutely. Yeah, there would be, in some cases there are monogenic disease mutations and pathologies that we know ought to have an effect, and we're really excited to see if that holds up, and how that holds up and what their phenotype is when looked at in this sophisticated way. And then there are other, more mysterious mutations that would be really excited to see a phenotype in. Kaytlyn Gerbin: Our goal at the institute is to build the tools and provide the resources to the community to be asking these kinds of really detailed, very interesting questions. I mean, I think there's definitely interest in doing some of that work here, but our main focus is to design the tools and the methods and make that all available to the public as soon as it passes our QC. So, that's the, those are the kind of thing that I think the community will have a big impact on, testing these kinds of things in their own systems given you know, new tools and ways to do it, so. Andrew Landstrom: Right. Brock Roberts: Our whole, our whole ethos is to cooperate and to facilitate. And rather than compete with other investigators, we want to make things possible and that are shared and open. For example, our list of genes that we went with to target, that was on open collaboration. We asked as many specialists in the academic community as we could to develop a consensus of what would be the most useful markers for different organelles. And we chose those proteins and genes. So, we're really trying to be collaborators, as best as we can. Andrew Landstrom: Are there specific examples of collaborations that you've felt were particularly productive or yielded some new exciting insight? Kaytlyn Gerbin: Mm-hmm (affirmative), yeah. I could give you a few examples. So, Doctor Ben Freedman, who is at the University of Washington, he is working on kidney research. And so, he has a few of our cell lines, he actually, it's convenient because we are located right across the street from each other, so we'll see them fairly often, but, yeah. So, he works on kidney research with the different cell lines and he really wanted to get the cells into a 3D context. So, he is working on a lot of different tissue engineering to study developmented disease. And so, he's also starting to make his own, their own mutations in the cell line, and so that's been, at least so far, that's been one collaboration that's I think has really been very powerful. And it's cool because we don't have the bandwidth right now to be looking at kidney organoids, but I think it's showed, kind of, the power of these kinds of cells and tools that, you know, when you have that you can do the live cell imaging with different structure within the same kind of organoid and you can get a lot of information, and so ... Andrew Landstrom: Yeah. Kaytlyn Gerbin: That, that's been fun to see develop. Another one that I know, Chris Chen at at Boston University is using our lines and is making cardiomyocytes with them as well and looking at the effects of patterning. And patterning is something that we also planning to do here, but that collaboration has been great to kind of get things going. And we've also been working closely with a group at the University of Washington, Georg Seelig's lab, who's developed a new way of doing single cell RNA sequencing. And so, that's been fun, we've been looking at that with stem cells and then cardiomyocytes to, kind of help, help us figure out what the different states that the cells are in. And then that is going to help and form, kind of, what future tags we might do or when, when to do imaging or kind of what protivations we want to put the cells through. Andrew Landstrom: That sounds like you're spanning the gamut really of downstream experimentation on these lines. Brock Roberts: Yeah, and we've also had a lot of people buy the cell lines. Kaytlyn Gerbin: Yeah. Brock Roberts: Acquire them through the Coriell, we hope that each case of their productive application toward different research questions could be defined as a mini collaboration. Maybe we'll hear from some of these people. And in some cases we have, and there may be more things that spring out of that. Kaytlyn Gerbin: Yeah, I think like, because the lines are available through Coriell it's, it's a little early to start seeing publications from the stuff, because we're a pretty new institute, but we do keep track of where the lines are going and, I mean it's exciting to see, I mean, pretty much all throughout the world there's people ordering the lines and starting to do research in a lot of different kinds of systems. Brock Roberts: Right. Kaytlyn Gerbin: So, we don't always necessarily directly collaborate with the people that are using the lines, but a lot of times we do hear from them or we'll run into people at conferences or something who have been using our lines. So that's really fun to see that its, our, you know, the work that we're doing here is actually producing things that people in the community are finding informative and useful. So, that's always fun. Brock Roberts: It's still so early in this project. I mean we're just at the beginning of a lot of collaborative potential. So, we really hope to see this take off. Andrew Landstrom: Yeah, and if people listening want to collaborate or want to learn more, how can they learn more and how can they get ahold of you all? Brock Roberts: Oh, hold on, I think, first of all, we really want to funnel people to our website. We think it's a really great resource and at that allencell.org you can contact us through that link. We look forward to hearing from you. Kaytlyn Gerbin: Yeah, so you can start with the website there. And as we mentioned before you can find all of our cell lines, plasmoids, protocols, etc. on this site. And we've also started to do a few more instructional videos, and so those are coming up on the website, too. So, some things, you know, especially as more groups are starting to use the lines, we do have the detailed protocols, but I think groups that maybe haven't done stem cell culture before or haven't worked with these kinds of IPS lines before, we're trying to provide as much content for people to make it easy for them to do the research. So we're starting to do more, sort of instructional videos. Brock Roberts: Yeah, and we seek this out. We want to hear from people. It's not a bother. We're trying to get as much, we're trying to get the, we're trying to branch out and communicate as extensively as we can. Kaytlyn Gerbin: Actually, one thing I just thought of that I want to add in her is that we have started to work with a few stem cell cores. And so, right now, I mean- Brock Roberts: These are core facilities at universities. Kaytlyn Gerbin: Yeah, stem cell core facilities at, yeah, exactly. So, part of trying to distribute the lines is that if we can, you know, individual investigators could get our lines from Coriell and get the licensing and everything to do that in their own lab, but it's, I think, going to be really great if we get some connections with the stem cell cores because then once we can provide the lines to them, they can distribute them to investigators that are part of the core. And so, so far, we already have agreements in the works with University of Washington, UC Berkeley, and then the Salk Institute, but this is something that we're really hoping to expand this year. So I think, in particular, you know definitely contact us if there's questions about the lines or anything, but if you are part of a stem cell core at a university and you think that people at the university would be interested in using our lines we're working really hard to make, you know get, kind of, packages, protocol packages and everything available so that we can get these lines set up in the stem cell cores. Brock Roberts: Right. Andrew Landstrom: Well Brock and Kaytlyn, thank you so much for joining me. What an incredible resource that you all have created, and I especially appreciate how open and transparent you are with your lines and your quality control and how you just really, you know, try and strengthen collaborations and to start new ones. Brock Roberts: Thank you very much for the conversation. Kaytlyn Gerbin: Yeah, this has been fun, thank you. Jane Ferguson: I hope you enjoyed listening to this episode of Getting Personal: Omics of the Heart. Let us know how we're doing by leaving a comment or tweeting at us at @circ_gen. We love to hear from you.
Transcript for January 2018 Podcast Circulation: Genomic and Precision Medicine Jane Ferguson: Hi, everyone. Happy New Year. You are listening to "Getting Personable: Omics of the Heart". I'm Jane Ferguson and this is episode twelve from January 2018. This month I have some exciting announcements to make. The journal formerly known as "Circulation: Cardiovascular Genetics" has a new name. As of this month, the podcast is brought to you by "Circulation: Genomic and Precision Medicine". We're still publishing papers focused on cardiovascular genetics but as genomics and other omics have expanded our scope has grown to so much more than just genetics. The new name, "Genomic and Precision Medicine" signifies the journals focus not only on genetics, but also genomics and all the other omic technologies and the feel of precision medicine. Along with the new name we have a new editing team. Dr. Kiran Musunuru, an associate professor of cardiovascular medicine and genetics at the Perelman School of Medicine at the University of Pennsylvania has officially taken over as editor-in-chief. He has already been implementing new initiatives to allow the journal to serve authors and readers even better. Along with create original research articles you can find accompanying editorials, videos and interviews with authors, including the interview we're featuring in this month's podcast. Finally, while "Circulation: Cardiovascular Genetics" was published every two months, "Circulation: Genomic and Precision Medicine" will now be published monthly. So, you can look forward to a new issue every month and even less time waiting for the newest research to be published. Check out the latest issue and all of the new material at circgenetics.ahajournals.org and follow us on Twitter at Circ_Gen. Now, along with the name change for the journal, we have another name change in the pipeline. Our AHA Council, Functional Genomics and Translational Biology, is also being renamed to "The Council on Genomic and Precision Medicine". As with the journal name change this better reflects the evolution in our scope and focus. This name change will be formalized in the coming months. So, if you are one of the many people who could never remember what the acronym FGTB stood for or what order all those letters came in, your struggles will soon be over. We have a number of interesting papers published this month, including an article by George Hindy and colleagues on how smoking modifies the relationship between a genetic risk score and coronary heart disease; a mendelian randomization study from Jie Zhao and Mary Schooling on coagulation factors and ischemic heart disease; an exome wide association study of QT interfolds from Nathan Bihlmeyer and colleagues; a study on genetic testing of cardiac ion-channelopathies and still births from Patricia Munroe and colleagues; and a genetic study of cardiac disfunction in Duchenne Muscular Dystrophy from Tetsushi Yamamoto and colleagues. You can also catch up on the genetic cardi-oncology literature with a review by Marijke Linschoten and colleagues on chemotherapy related cardiac disfunction. And read a clinical case on left-ventricular non-compaction by Vi Tang and colleagues. Finally, we also have a scientific statement on the use of induced pluripotent stem cells for cardiovascular disease modeling in precision medicine by Kiran Musunuru and colleagues. Moving on to our feature article, Andrew Landstrom, an early career member of the Genomic and Precision Medicine Council, formerly FGTB, talk to Guillaume Paré and Sébastien Thériault about their article published this month entitled, "Polygenic Contribution in Individuals with Early Onset Coronary Artery Disease". In this paper, Dr. Thériault and colleagues report the use of the genetic risk score which improves on our ability to predict very early onset CAD. Listen on to the authors talk more about the background to this study and what they learned along the way. Andrew: Welcome. My name is Andrew Landstrom, an assistant professor in the Department of Pediatrics, Section of Cardiology at Baylor College of Medicine. I am a member of the early career committee of the American Heart Association Council on Genomic and Precision Medicine, previously the Council Functional Genomics and Translational Biology. I'm joined today by Sebastien Theriault, assistant professor in the Department of Molecular Biology Medical Biochemistry and Pathology at Laval University, and Guillaume Pare, the Canada Research Chair in genetic and molecular epidemiology, assistant professor in integrative health bio-systems and associate professor of medicine at McMaster University. Guillaume: Hi. Good morning. Andrew: Well, I'm wondering if we could just start by introducing ourselves maybe a little bit more thoroughly than I just did and talking a bit about your research paper and what brought you to this as a research question. Guillaume: Absolutely. So, this … [inaudible] and thank you for having us. My name is Guillaume Pare, and as stated, I'm an associate professor at McMaster University, and I would say like my longstanding clinical interest is about individuals and families with very early coronary artery disease and heart disease. And this really was the basis for this project and to try to understand why do some people in family are afflicted by this disease when we cannot find any of the conventional risk factors. And as Sebastien came to join me and this endeavor, and spent two years with us here at McMaster and was instrumental in getting this project off the ground. Sebastien: Yes, exactly. So, I was a physician trained in Quebec City and I went to McMaster University as a research and clinical fellowship. And that's where I did some cardiovascular clinics with Dr. Pare and that's when we noted that some patients with early coronary artery disease didn't have much explanation for their disease. So, that's how this project stem, that we wanted to understand what was going on and we thought that really genetic factors could be involved. Andrew: And speaking of these genetic factors, in fact, you established a genetic risk score as sort of a way of aggregating a large number of genetic variants into a single prognostic risk indicator. How did you come up with the score, and where did these genetic variants that you aggregated come from? Sebastien: So, the results of many of our studies looking at the association between common genetic variants and coronary artery disease have recently been released. For this study, we use the variants identified in the latest CARDIoGRAM for C4D consortium meter analysis, which includes more than 60000 individuals with coronary artery disease and 120000 individuals without coronary artery disease from a total of 48 studies. Most of the participants in these studies were European. And so we decided to use the independent variants that were associated with the disease in that very study and look if we could predict early coronary artery disease in some patients. Guillaume: Andrew, maybe I'll backtrack a little bit. The initial idea about the gene score, first of all came from the observation that a lot of the patients who we're seeing do not have any traditional risk factor. The second observation is that we already knew that genetic risk scores are predictive of coronary artery disease. But the key question is, is it possible that there are people at the extreme of severity of a cardiovascular or genetic risk score that could be at much, much higher risk of having the disease. And this is what the hypotheses really that we wanted to test is whether these genes scores they could identify people that clearly have outlying risk, outlying genetic risk of having the disease. And to explain, the patients that we were seeing a deflation in the clinic will clearly have an outlying risk of disease because they have a First Earth attack or multi vessel disease in their 30s or 40s, and we thought that this cannot be just like bad luck, there had to be some ... and this something is really most likely genetics. We cannot put a finger on it because all the known mutations that we know could cause this, well, we're just not finding them. Andrew: Sure, sure. And there's certainly having a large number of genome association studies, which have implicated a number of common variants and not so common variants in coronary artery disease. So, is this where some of this idea behind the genetic risk or was initially thought of? Guillaume: Absolutely. And I think you know ... and this is where Sebastian really came in and to really like look at this literature, to feel like the variants that went in into the score. Andrew: And certainly to go to your earlier point, it seemed like you were saying early on that coronary artery disease would be a great phenotypic model to explore this question in, mainly because it would seem that at that age, with that severe disease, that it must be something innate to that person, and genetics would certainly play a role. Guillaume: Absolutely. And to me, it's more than simply scientific because we see these patients at our clinic and we've got a lot of ref roles for these patients, and we really feel for them because they're really young people, and I think like when we think about genomic and like preventative medicine having an impact, I cannot see a greater impact than preventing a first heart attack in the 30s or early 40s. So, this is a ... it's a very vulnerable patient population. It's also a patient population that has a lot of questions about why this might be happening to them, and often what we see is that, I think everyone feels that clearly there's a genetic component, and one, a loved one has first attack in his or her 30s, this raises questions for the whole family really, and it clearly sends a shock wave in the family, and everyone, I think rightfully, is quite scared of having the disease and the fact that there is no answer for these people, to me is a huge unmet clinical need. And it's just for the sake of providing people with answers. Andrew: Yeah. Absolutely, I think it's certainly a clinically relevant question that you attempted to answer. And to try to get to this a little bit, and you utilized a large UK-based biobank as your primary study population to establish this risk score. Can you tell me more about this biobank and what sort of data you were able to obtain from it? Sebastien: Sure, I can speak a bit about it. So, the UK biobank is a large prospective cohort of about 500000 individuals between the age of 40 and 69, with an average of 58 years, and they were recruited from 2006 to 2010 in several centers in the United Kingdom, and the general objective is to study the effect on the environment and genetics on health. And what's interesting is that the data is made available to the research community worldwide following registration process. And the data in that includes a very vast amount of information, from questionnaires, specific evaluations, such as height, and weight, and aging data, and the diagnosis from the participants, medical charts, in addition to the genetic data of course. And for this study we used the first release of the genetic data, which included information on about 40 million variants in about 150000 individuals, and selected the individuals who had a diagnosis of early coronary artery disease, so aged 40 or less for men, 45 or less for women, and then it underwent a reversed relation procedure in order to identify patients with obstruction in coronary artery disease, and we used all the other participants as controls. And that's basically leveraging this huge amount of data that we were able to confirm the fact that patients with early coronary artery disease, some of them very high and pathogenic components of their disease. Andrew: That certainly sounds like a really amazing, both biobank and cohort of information that could be utilized. Such a huge sample population with so many clinical variables as well as genetic variables and collected prospectively. What a great resource. Sebastien: Yes indeed. Guillaume: It's a fantastic resource and to me, this type of initiative it's a game changer to accelerate research, because with these data being made available, then it's really up to testing new bold ideas to try to improve our understanding of this disease. So, I think you know we have to say kudos to United Kingdom for financing this this great cohort and making it available to researcher worldwide. Andrew: And you didn't just stop there. You also utilized a local cohort as a foundation cohort for your study. Could you speak a little more about that? Guillaume: So, that's interesting because this cohort really stems from the patients that we've seen at the clinic. And essentially, we felt this was this huge unmet clinical need. To better address causes of disease, and these roles that's barely a disease. And then we said, well, if we were to do this, let's do this formal, and let's do this properly and collect the information and samples and everything, and we had a very enthusiastic response from our cardiologist, and international cardiologist colleagues that really helped us identify these early cases and send them to us and in our study. And so these are local patients. These are people that we care deeply about, and that's really want to make a difference. And again, you know, when Sebastian was with us at McMaster, we were seeing these patients together, and maybe he can add some of the details there if you want. Sebastien: Yeah. Just to specify again, these were patients at the very early coronary artery disease, for age 40 or less for men, and age 45 or less for women. And these were patients without the clear secondary cause of their disease. Most of them were clueless about what were the factors that caused the disease outside a few risk factors such as smoking or hypertension, there wasn't clear explanation as to why they had such early disease, and we could see that it was a struggle to try to understand and then see if there is a risk for their family also. So yeah, it was really interesting to find an explanation for some of them, and we did report the findings to a few of them who seemed to have polygenic contribution to their disease, and it did make a difference. They were quite happy to at least have some kind of an explanation to what was happening to them. Guillaume: And I think that one thing that I think was striking to me when doing this is that when we started to formally collect family history in these individuals, we just realized that and in many, if not most of them, the family history is really striking. And these are folks that clearly has a very severe individual disease, but when we start asking about their brothers, and sisters, and parents, and uncles, you just realized that coronary artery disease was just all over the place and was very aggressive and early. And I think to us, this gave us purpose in this project to say that, 'Yes, we have to do something about this,' but also, I think it also reassures us that our primary hypothesis was right in thinking that there has to be a genetic component that goes beyond just having bad luck, and this genetic component was expressing itself by the family history that we saw. And a further clue that I think we might be on the right track is that the pattern of inheritance didn't shift one of the single mutations that aggregates in a family and that can explain the disease. So, the disease was more diffuse and oftentimes it was both from the paternal and maternal branch of the family without a clear genetic pattern that would be more in line with the so-called mendelian disease, where a single gene mutation causes the disease. And I think really that puts to us in the mind that we might be looking at the different modes of inheritance, and this is partly how we came with this idea of looking at gene scores in these individuals and families. Andrew: So certainly a close clinical connection to the patients and their families that you're trying to risk stratify and certainly, it sounds like clinical suggestion that you were dealing with something genetic and inheritable, but not necessarily mendelian, where one gene defect leads to say an autosomal balanoid express disease, more of a polygenic family history exactly. Guillaume: Exactly. Andrew: And so with these two scores and this genetic risk score, what exactly did you all find? Sebastien: So first we found that participants from the UK biobank who had this early coronary artery disease had a very significantly higher number of common genetic risk variants. So the score was very significantly higher in these patients. And what was interesting too is that the increase in risk that was associated with the score was independent from traditional risk factors such as smoking and high blood pressure. And when we looked in the local cohort with early coronary artery disease, out of 30 participants that were involved, we found seven with a significant polygenic contribution, which we define as, a two-fold increase in risk, and one of the participants actually more than six-fold estimated increase in risk. So we really did identify an explanation for some of these participants with the early coronary artery disease. Guillaume: And I think this was maybe a bit of a eureka moment to see that some of these individuals actually had a much, much increased risk of disease based on the polygenic risk score, and this really was the primary hypothesis that when looking at extreme of disease, which is what we're looking at, we might find extreme of genetic predisposition. But the one thing I thought that's quite striking is then we went back to think all that. And to try to put this in perspective with what we would usually do in these patients that we've done already, and to look for mutations that cause familial hypercholesterolemia. Familial hypercholesterolemia is a disease of cholesterol metabolism that leads to a much increased concentration of cholesterol and early coronary artery disease, and a discovery that led to a Nobel Prize for Goldstein and Brown, back in the day, and really like, up to this point, when we see people with early disease clinically, this is what we will be looking for. And certainly, there's a lot of these individuals that have very high cholesterol and a lot of them is due to familial hypercholesterolemia. But it's a minority of patients really. It looks like we're having an association and this gene score concept is really panning out. But I wouldn't compare to familial hypercholesterolemia, and I guess that the results were kind of surprising to us and I think we had to take a step back and think about the implications. And I don't know, Sebastien do you want to describe these results or ... Sebastien: Yeah, sure of course. So we've looked at how frequent this polygenic contribution to coronary artery disease could be. So we look at the prevalence of high genetic risk or that would cause a risk similar to familial hypercholesterolemia see the ratio about 3.7, and we realized that one in 53 individuals had an increasing risk that was similar. So that's almost 2% of the population, and that is way more frequent than the actual prevalence of familial hypercholesterolemia, which is one in 250. So in other words, the polygenic contribution could be almost five times more frequent than familial hypercholesterolemia. Andrew: But yet not all of those individuals manifest as disease, which sort of hits as something that's a common thread in genetic association studies where we're trying to describe sort of multifactorial disease en points with finite genetic and a whole spectrum of acquired disease, required lifestyle modifications and things. So no model is 100% perfect, and so where do you think that additional variation lies, either in the reduced penetrance of some of these disease phenotypes, or are there other genetic loci, or are these all secondary to acquired changes that happen, or where does some of that variation lie? Guillaume: Well, to me I think there's two parts to this question. The first one is that I see the cells study as in some sense, proof of concept, to look for the concept of very high burden of polygenic risk as a mendelian equivalent really. But the fact is that, especially with the new discoveries and the genetics of coronary artery disease, the gene scores that we've been using for this study could be much improved. And I think the concept is there, but the gene score could be improved, and I think they will be improved and I think in three, four, five, ten, years from now, they're going to be even better because we will have many more variants that we know are preceded with coronary artery disease and that might be upwards to 1000 variance, for example will have much better gene score I think we'll have much more predictive gene scores. So I think the concept is there, but I think it's going to improve, with the years is only going to get better. And I think part of this missing risk, if I may, is due to the fact that we're missing a lot of genetic variants associated with coronary artery disease, and I'm very confident that the community will find them in the years to come. I think the second part of the study is that, that being said, I think genetic risk is obviously important but we shouldn't neglect also classical risk factors. And a lot of [inaudible] … they did have the classic risk factors and that was a fairly high proportion of smokers, and a few cases of diabetes, and I think that individually, this risk factor wouldn't be enough to explain the aggressiveness of this disease. But I think the fact that we do find an enrichment for these factors also give us ... I think it feeds the idea that it's not only genetics and that even in these individuals classic risk factors do matter and trying our best to decrease the burden of these risk factors on a community and its role family level is probably also very important. Sebastien: I'd also want to know that there's an environmental part that's involved even in these individuals with high genetic risk. And as he just mentioned, we did notice a high proportion of traditional risk factors in patients with early coronary artery disease even in some of them with high polygenic score, some of the environmental factors seem to be also involved in their disease. Guillaume: And to some extent I think that's going to be an interesting research question, in these individuals with very high polygenic burden, do traditional risk factor, do they at the time, are they stronger or weaker, is there a synergistic effect between, for example, smoking and being at this extreme of the polygenic risk? And these are kind of open questions that we couldn't address in the current study but I think will be interesting to see in the years to come. Andrew: Absolutely. I think there's definitely a road ahead of us but this is definitely a step in the right direction. What are some of the practical applications of this genetic risk scores, either from your study or from others in the identification of individuals? Is it something that could be used for primary production? I mean, in theory, this could be done at birth. You could be screened for these genetic variants and the risks will be calculated within the first days of life. What do you think are the practical applications of this and where is this fit into a rapidly expanding world of clinical genetics? Guillaume: Well, I think you know what you've just described is exactly how I see the future, and I think that if we want to be consistent, and we consider folks with a familial [inaudible] mutation to be at higher risk, I think that someone with a predicted polygenic risk of twofold, threefold, or fourfold increase risk of coronary artery disease should definitely be put in a higher risk category when it comes to primary prevention irrespective of other risk factors, or maybe like in combination with these other risk factors, and I think should be treated accordingly. And as we see, these are people are very aggressively affected by the disease, and I think the sooner we could identify these individuals at high risk and try to intervene to lessen as much as possible this risk, I think we will do these individuals and families a great service. So I think it's definitely a case for primary prevention and especially in a world where genomics is more clinically prevalent and used, also we see a role for this and the role that's already affected. And to me personally, I see great value in providing people with answer on why they've had an event and probably providing an answer not only to them, but also to their families. Andrew: And so if something like this were to be able to be applied broadly in the clinical arena, what sort of steps do you think need to happen from this point forward to make this sort of testing ready for prime time? Guillaume: This is a great question and I have to say that my passion I would say is to bring genomics to the clinic. I think there's a long road ahead to make this happen. But I think there's two main obstacles. The first one is that I think there's a knowledge gap between people that do this 24/7 like me, and I think you know the rest of the community and that there's been so much rapid progress in the field of genomics in the last few years that I think there's a lot of education to be done for people to catch up and just the concept of polygenic risk. I think only a minority of clinicians will know about this and very rightfully, because right now it's in the realm of research papers. So I think to make this happen, there's a huge role in education and awareness. I also think that our hospitals ... or maybe it's a Canadian thing, are not prepared just for the flow of information and how to derive the routines commercially, and probably how to handle these highly multi-dimensional data and to be able to take the right information out of them and I think in this world, I would think that probably the best way to do it is to do it in a way that these gene scores can be updated, the science progress. But we're so far away. Sometimes I feel that our hospital system is struggling to provide [inaudible] time to clinicians. And I'm just thinking without the prevention or how to handle something as complex as polygenic score, in this case we barely had like all the plugs in 200 variants, but you could clearly imagine like genetic risk scores being done with hundreds of thousands, if not millions of variants and will bring a whole new set of challenges. Andrew: And Sebastian, do you have a perspective on this? Sebastien: Yeah. I would just add that this knowledge is in the research community but to really put that into the clinic there's old setting, you have first to interpret the results and also to disclose the results to patients in a way that they can understand and that wouldn't create unnecessary anxiety, but more give them informed and an informed view of their health. So there's this also translation to the patient that needs to be evaluated and developed for it to be used to mainstream I would say. Guillaume: And I think the classic tools like publications also presentations and meeting and even reaching out to the cardiology community to start discussing these concepts will be important. And clearly it's a big shift from just classic genetics and even familial hypercholesterolemia, I think there isn't a lot of awareness, I don't think there's enough awareness as far as I'm concerned. And then we're bringing new concepts that might be even further remote from what people have been taught about genetics and score, it's going to be a huge challenge, but we have to. And I think the great thing about the medical community as far as I'm concerned, is that every time that there's been something that was worthwhile to do clinically, the community has always come around and making sure that these things are implemented and made available and everything. So I'm also very confident, but I think there's a great challenge ahead as well. Andrew: It sounds like the challenge has a potential for great benefit and if proper partnerships between the clinicians, and the geneticists, the scientists, and the patients and their families can all sort of come together to establish a path forward for this type of information to be applied clinically. Guillaume: Yeah, absolutely. And I really like that to add there that you've put the clinicians, geneticists, and patients as well. I think it's very important, patient advocates are a very important part of the equation here. Andrew: Going forward, are other disease processes besides early onset coronary artery disease that you all feel might benefit from a similar polygenic risk? Sebastien: The recent studies show that a lot of complex traits seem to have polygenic origin. So traits like hypertension, diabetes, obesity, atrial fibrillation, for example, they show a similar genetic architecture where there seem to be combinations of a very large number of common variants that explain the genetic risk. So it's a big number of variants with smaller effects that seem to be responsible for the appearance of these complex traits. So this concept could potentially be applied to a lot of different diseases. Guillaume: I think I would maybe just go even one step further, but I really have the feeling that most late onset disease actually has a polygenic architecture, which means that similar polygenic risk score could be done targeting the extreme of distribution to look into this. I mean obviously, I think metabolic traits, diabetes, hypertension as Sebastien mentioned, but probably why not some cancers, or [inaudible] or any of the large number of disease where a polygenic inheritance either has been proven or is highly suspected. So I think that we will hear a lot of polygenic risk score in the future, and I might be biased here, but I think it might become a staple of clinical practice that people will be looking at polygenic risk for a number of disease. And I think the great thing is that now that we've got genome-wide genotyping that is really affordable and we can type with statistical imputation and tens of millions of variants, then I think one concept is that we only have to genotype once and then we can derive these polygenic risk scores for ... why not a dozen diseases that are important and are actionable and really like turbo charge primary prevention by using this information. I might be getting ahead of myself, but I really think that this is something that we might see and that for us, we should see. Andrew: And certainly that seems to be the way that at least the literature is trending, definitely towards more, and more data and more, and more exploration into a number of diseases that may have mendelian inheritance pattern but may also have a significant component that's polygenic, particularly like you were saying in those individuals that present at the extremes of severity. So I think it's certainly where we're heading. Is there anything else that either of you would like to share about the study that you feel be important? Guillaume: I think we've covered a lot of ground here, but perhaps the one thing is just to reiterate that this is a proof of concept, but I really think that the act of polygenic risk score will continue to improve for quite a while, and as it improves, it will only get better. So we can only move forward with this in terms of the accuracy of the prediction, and I think that that's a great thing and hopefully with this we'll be able to better predict risk. And the other thing as well is that, I would say that at this point we can identify people at risk. And I think it's great because it provides answers, we can target known risk factors. But I think a big part that's still open is, can we use this risk to derive like more individualized treatment, or to actually choose what should be the best way to prevent events in these individuals. And again, I don't think we're there yet but this is something that I think it's worthwhile investigating in the future and maybe trying to dissect this polygenic risk and to see maybe it falls in one or two categories or maybe it's a global risk, and these are all open questions that I think are important, but that are still very much of a mystery right now. Andrew: Sebastian? Sebastien: I think we've covered a lot of ground like you said and I don't have too much to add. Otherwise, I think we'll see a lot of these polygenic risk scores in the future and for risk improvement even to understand better the physiology of disease. These are very important concepts. Guillaume: And I think you know the common approach of physiology is good because these gene scores they don't seem to be associated with classical risk factor. In our study, rather weak association with blood pressure and families history. Now, family history is kind of logical. Blood pressure suggests that perhaps there's an overlap between the two pathways, but clearly adjusting for blood pressure like that only slightly attenuated the predictiveness. So basically what this is telling us is that this polygenic risk score seems to be acting through pathways that we don't know of, that we're not measuring clinically, and I think that’s a big part of the future would be to say, 'well, what are these pathways, and can we actually assess them? Are there other cholesterols out there?' Cholesterol is great because it's causal, we've got synthetic pharmachemicals, you've got tools to decrease it, and we've got fantastic evidence that decreasing cholesterol decrease risk. Is it possible that there's other pathways that are there and that we could do to sign, and I think all of this gives us great clues that this might be so. I think as happens quite often in science, we start with an hypothesis and we try to address it the best we can, and at the end of the day, here I guess we've been lucky because it kind of panned out, but it also opens so many more questions about; So what are these other pathways that these genetic risk scores are capturing that we're not capturing clinically right now. And how could this lead to better treatment, and how to implement this and everything, and I think this is really what's so exciting about doing research, and as far as I'm concerned, doing research that has an impact on people's lives and trying to improve people and provide answers to people. Andrew: Sounds like a great summary of the rationale for doing this. Thank you very much for joining me and for sharing your work. Guillaume: My pleasure. Sebastien: Thanks. Jane Ferguson: Thanks for listening to "Getting Personal: Omics of the Heart." You can subscribe on iTunes to get each new episode delivered straight to you. And we'll be back with more next month.
Jane: Hi. Welcome to episode three of Getting Personal, Omics of the Heart. I'm Jane Ferguson and this podcast is brought to you by The Functional Genomics and Translational Biology Council of The American Heart Association. In this episode, I talk to Jonathan Mosley about an interesting genetic method he has developed to look at shared genetic contributors that influence risk phenotypes, as well as disease risk, which can be used to integrate data from prospective studies with large scale electronic health record data. We also highlight a recent AHA scientific statement on genetic literacy and Nevine and I discuss the latest in precision medicine. Our large hurdle in implementing precision medicine will be to increase understanding of genetics and genomics amongst healthcare providers. Sima Mittal, Karen [inaudible 00:01:11] and colleagues tackled this issue as part of a recent AHA scientific statement published on behalf of The Council on Functional Genomics and Translational Biology, The Council on Cardiovascular Disease in the Young, The Council on Cardiovascular and Stroke Nursing, The Stroke Council, The Council on Lifestyle and Cardiometabolic Health and The Council on Quality of Care and Outcomes Research. As the promise of genetics guided treatments is becoming a reality, cardiovascular healthcare providers often struggle to stay up to date on this large and rapidly advancing field. Although there is a need for more dedicated genetics professionals, such as genetic counselors, it is also important that all cardiovascular practitioners maintain core competencies in cardiovascular genetics. This statement entitled, "Enhancing Literacy in Cardiovascular Genetics" was published in the October 2016 issue of Circulation Cardiovascular Genetics and outlines useful information for the cardiovascular practitioner when considering genetic and pharmacogenetics testing and includes pointers to resources for enhancing knowledge and genetics and genomics. As always, this and the other papers mentioned in this episode are linked on the podcast website at fgtbcouncil.workpress.com. Hi, Jonathan. Thank you for joining. Jonathan: Thank you, Jane. I'm happy to be here. Jane: Maybe first I'll give you a chance to introduce yourself. Jonathan: Sure. My name is Jonathan Mosley. I'm up here at Vanderbilt University. I'm an instructor in the department of medicine and do both a little bit of clinical work related to hypertension but spend most of my time doing research, and in particular genetic research, using Vanderbilt's integrated electronic health record and biobank data system we call Bioview. Jane: Which is a really fantastic resource and you've been doing some really interesting things with it. Today, I wanted to talk about sort of an interesting method and the application of that method that you've developed. For our listeners, there's a link to these papers on the website but you can find them. We're going to be talking about two different papers. One of them called Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data and was published in the December 2016 issue of Circ CV Genetics and then a second sort of related paper entitled Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes is in the current issue of Circ CV Genetics, which is the April 2017 issue. Jonathan, maybe to start you could tell us a little bit about sort of your thinking behind the development of this new method. Jonathan: Yeah. I can kind of give you a rationale. I'll focus on that first paper initially. The content area really relates to ischemic heart disease or coronary heart disease, so disease due to blockages of your coronary arteries. This disease in particular it's really I think an epidemiologic success story. Really over the last several decades there's been a pretty marked decline in death due to coronary heart disease. A good portion of that can be attributed to the fact that we've really started to understand this disease and understand risk factors. I think the framing in studies is always brought up at the prototype but study these prospective studies like Framingham. Help us identify risk factors that modulate risk of coronary heart disease. By changing behaviors like smoking and treating cholesterol levels, we've been able to now really change the epidemiology of this disease. There's also been some other changes in society I should add. We've become a much heavier society and so this also modulates our risk of coronary heart disease. If it were cheap and easy to long perspective studies, you could imagine that it would be desirable to start a new Framingham today kind of under the notion that the epidemiology of this disease has changed. Let's create a new cohort that reflects today's epidemiology so we can really target the prevalent risk factors that we're seeing in our population right now and really try to target those risk factors. It's not really a feasible approach. Starting a perspective study is constrained for quite a few reasons. Jane: Right. None of us have the funding for that. Jonathan: Yeah. In terms of cost and then there's always an inherent lag also in these perspective studies in terms of you have to wait for outcomes to occur too. Kind of a rationale underlying this first paper is is there a quicker way which we could try to get the outcomes that we might otherwise expect from a perspective study? At Vanderbilt, we have this data resource that I mentioned earlier called Bioview. A large amount of the health information and data related to clinical encounters are captured in electronic form and this is available in a de-identified form for research. We have a dataset of over two million clinical records or records on two million individuals that we can use for research. About 235,000 of these individuals also have DNA available. In particular, we can do research looking at genetic modulators of disease. In this dataset that I have, I can quickly identify thousands of cases of various outcomes like myocardial infarctions or ischemic heart disease or diabetes. We can identify far more of those outcomes than you'd except really in most prospective studies. They're not large enough to observe that many outcomes but really a limitation of these is that we don't collect standardized baseline measurements within individuals who are captured in electronic health records. In other words, they're just encountering the health systems for different reasons but there's no protocol that describes specific baseline data that should be captured. It's really not feasible to do a perspective study or even a retrospective study despite having all these great outcomes. The rationale for the current study was really can we take all these outcomes that we're observing in institutions like Vanderbilt and others and perhaps get the baseline risk factors from another source. In this kind of imagined study design, you take risk factors that you're able to measure under epidemiologic conditions and then see whether they're associated then with these outcomes that we're observing in our EHR systems. That's really the study design. That's really the hypothesis that I was exploring. Could you implement this particular study? Jane: That's really interesting. I think it's a great way to sort of maximize the availability of data from different sources to sort of take what you need from different studies and combine it. For this kind of study, if you're combining data from two different studies, how similar do the demographics have to be? Do these have to be from people in the same country, the same racial group? How important are those sort of factors? Jonathan: Using standard epidemiologic methods, it's not possible obviously to link kind of risk measured in one population and outcomes measured in another population. Really, emerging genetic methods allow us to do this. What we're doing is we're capturing or using genetics really to measure or to link these risk factors in one population into another population. Issues like race are important. We certainly know that there are racial differences that if you don't account for these they can really lead to a lot of confounding and unexpected findings. It's important that you can get populations that are genetically similar for the method that we used. Jane: Yeah. Maybe we can go into the results of what you found in the first study looking at ischemic heart disease genetic risk. Jonathan: Yeah. Let me just kind of tell them a little bit about the genetic method that we used to associate these. What we did is we used a method measure the effects of large numbers of snips on a phenotype. This method is fairly similar to or has a lot of things in common with kind of very old genetic methods where you'd estimate heritability. Often, you'd do this by you'd collect related individuals and you wouldn't directly measure their genetics or how genetically similar they were, but you could infer how much genetics they shared by knowing their relationship. For instance, a mother and a child share on average half their genetics. Then what you can do by kind of inferring how genetically similar individuals are, you can measure a phenotype and then estimate the contribution of genetics to that phenotype based on the shared. With kind of current genotyping methods and with appropriate sample sizes, now you can do similar types of analysis, but instead of inferring how genetically similar people are, you can actually measure how similar they are based on common snips. There's basically computations you can do across large numbers of snips to estimate how genetically similar they are. Once you have the similarities, then you can quantitate really how much of the variability in the phenotype can be modulated by genetics. That quantity is often called the chip heritability or it's really the heritability that can be due to large numbers of snips. You can estimate the heritability of two phenotypes but you can also measure the extent or quantitate the extent to which those genetics are shared between two phenotypes. This quantity is called the genetic correlation. What we did in this particular study is that we took baseline risk factors that were measured in the Eric population. There's about 8,000 unrelated individuals of European ancestry. We took baseline risk factors that had been measured in their first visit and then we took two different outcomes that we curated from our electronic health record dataset. This was the dataset that actually came from the emerged population, which is a collection of institutions like Vanderbilt that have come together to pull their resources in order to create larger datasets for study. What I did was measure then the genetic correlation between these 37 baseline factors measured in the Eric study and these two phenotypes. The first one I looked at was type II diabetes. I kind of think of that as a positive control. It's fairly easy to clinically diagnose or create a definition of diabetes. Basically, if you have a glucose above a certain threshold then you have diabetes. It's fairly easy to standardize. I expected that this phenotype would work well. What I did was I measured the genetic correlation between each of those 37 risk factors and type II diabetes and then I also did a longitudinal analysis within the Eric study where I measured hazard ratios, so a standard epidemiologic measure of risk, basically for each of these 37 risk factors to find out kind of the epidemiologic association between these risk factors. When I compared them, what I found was that genetic correlations or measures of genetic risk across populations very closely corresponded to the hazard ratios or a standard epidemiologic measure of association. Suggesting for type II diabetes, really the epidemiologic risk seems to be measuring the genetic risk of the disease. Jane: Yeah, which is interesting. I guess for diabetes, we know a lot of the risk factors but then can your method say how many sort of the risk factors are still missing for example? Would you conclude from this that we know most of the things that cause diabetes or could this method be used for finding novel biomarkers for example? Instead of looking at only 37 risk factors, if you looked at more do you think you would add a lot of additional information or do you think we already know sort of the bulk of what's increasing risk of diabetes? Jonathan: I think that's really kind of ... You hit on the important point. This analysis was done using well-known risk factors but really I think the ultimate goal would be discovery. I think there is a lot more discovery to be had, and in particular, whether a risk factor may or may not account for a lot of risk, you might identify new biomarkers that may help you make an earlier diagnosis that can allow you to then perhaps modify the course of the disease. Jane: I know in this paper, as well as looking at diabetes, you were looking at ischemic heart disease and finding a different pattern to what you saw for diabetes. Jonathan: Yeah. The conclusion from the diabetes was that diabetes that we're diagnosing clinically, that seems to be very similar to the diabetes phenotype that was identified in the Eric population. That didn't seem to be true of the ischemic heart disease where we actually saw that the risk factors, again, these 37 factors that we looked at, really the genetic measure didn't follow the epidemiologic measure nearly so well. We do see some important risk factors where they did follow each other well. For instance, high systolic blood pressure, high triglycerides increase your risk. Low HDL increasing your risk. Even smoking, which is interesting, how you smoke is actually genetically modulated, so we can measure smoking as a risk factor and see that smoking increases risk. There are some differences that caught us by surprise. For instance, LDL cholesterol, which is a strong known risk factor for ischemic heart disease, showed a genetic correlation of close to zero, suggesting that there is not a lot of shared genetics going on between modulators of LDL levels and ischemic heart disease in our population. That really caught us by surprise. Jane: Yeah, it's interesting. Of course, LDL is one of the risk factors that's most treated and that we're most aware of and we have a lot of different therapeutic options for treating LDL cholesterol. Do you think have we sort of reached the end of how much additional effect we can get from treating LDL? Are we already so good at treating LDL that any sort of additional therapeutic options down that avenue may not give us any additional gains in preventing disease or do you think there's some other explanation for why LDL did not appear to have a strong correlation? Jonathan: I'd certainly like to think that we're great at treating LDL here at Vanderbilt and it certainly could be one contributor is that we've perhaps attenuated the genetic effect of LDL. Unfortunately, kind of with the nature of the dataset that I used, I didn't have information on use of statins and other drugs that could give a sense of whether that was an important effect modifier. What the patterns of associations also shows in our dataset, again, this association with low HDL, high systolic blood pressure, high triglycerides seem to be a big driver, is that we really might have a population where the metabolic, this syndrome really driven being overweight and obesity, is really an important driver of risk in our population. It's possible that we might represent this changing epidemiology of the disease. Our other thought was that maybe just LDL doesn't work as a phenotype but we actually looked at another outcome, peripheral artery disease, and actually found a pretty strong association with peripheral artery disease. I don't think that there's an inherent problem with the phenotype. I think it's an excellent question and I think it's something that we're still trying to figure out the answer to. Jane: Maybe for ischemic heart disease, maybe treating the sort of obesity, metabolic aspect may be more important for helping these individuals. Jonathan: Yeah and I don't think our data supports stopping treating LDL but maybe it's possible that we can say we're doing a good job, at least in this particular population that we studied. Jane: Right, right. You've used this method and you sort of showed it really nicely with the ischemic heart disease and then the type II diabetes, and then in your more recent publication, you've shown how this can be applied to other phenotypes sort of in a more directed way. I'd love to chat about that a little bit. Jonathan: Yeah. In this paper, it's really running that same experiment backwards. Again, because we're measuring risk across populations and we're doing it based on underlying genetics, which your genetic risk is determined at birth, so we can either start with risk factors or diseases and there's kind of no temporality in this particular study design. In the second paper, what we did is somewhat run the experiment backwards where we took a risk factor or a biomarker really, in this case it was the PR interval derived from the cardiac electrocardiogram, and we asked the question for what diseases does the genetic risk driving that disease did those same genetics also modulate the length of your PR interval? What we found is one, with atrial fibrillation, and one was with measures really related to adiposity. Genetic factors which tend to make you heavier prolong your PR interval. The surprising finding here was that actually genetic factors which tend to shorten your PR interval increase your risk of atrial fibrillation. This seemed to at least conflict with a little bit of what's been published in the epidemiologic literature where the association has gone in the other direction. That was an interesting observation. Kind of our bottom line that we came to is actually if you go through the literature as a whole, there's really a U shaped relationship between PR interval duration and atrial fibrillation risk. We think that the genetics might be contributing to that lower end of the U or the inverse relationship. Jane: Yeah, which is really interesting. You have to be in that sweet spot right in the middle of not too long and not too short. Jonathan: Lifestyle factors. Again, obesity is always such a big driver of these things and metabolic phenotypes just tend to modulate a lot of these biomarkers. Jane: Right, right. Really interesting. For your next studies, maybe you'll be looking at other obesity related phenotypes I guess. Jonathan: Yeah but also, as you alluded to earlier, really the next step is to now start exploring more novel biomarkers. These studies allowed us to use pretty well described phenotypes and biomarkers to give us a sense of expectation of the results that we might see but now really we hope to move on to more discovery and novel discovery. Jane: I think it's a really exciting method. It has a lot of promise and it'll be really interesting to see where you go next with this. Jonathan: Yeah. Well, thank you for the opportunity to talk about it. Jane: Yeah, thank you so much. Hi, Navine. How are you doing? Navine: I'm doing well, Jane. A couple of exciting papers have been published in both Circulation and Circulation Cardiovascular Genetics I see. Jane: Absolutely. There's two that were published in Circulation in this month, so April 4th issue of Circulation that I thought were pretty interesting. They were sort of related to each other thematically. The first one is called Genetic Risk Prediction of Atrial Fibrillation and this was published by Steven Lubitz, Xiaoyan Yin, Emilia Benjamin and colleagues on behalf of the AFGen Consortium. What they did was they looked at variance associated with atrial fibrillation and they generated this AF genetic risk scores and then they looked at the association between this genetic risk score and incidence of atrial fibrillation in five prospective studies. That was almost 19,000 individuals. As well as looking at the relationship between this risk score and AF, they also looked at the relationship between the risk for stroke in a separate study of 500 stroke cases. What was sort of interesting is they were able to find that this genetic risk score was associated with the incidence of atrial fibrillation and it did add a little bit of additional discriminative power beyond just looking at clinical risk factors for AF but it was moderate. The addition of this genetic risk score didn't add a huge amount of additional predictive capacity. They did also find that this genetic risk score was associated with stroke. It's sort of an interesting example of using a genetic risk score to look at prediction of incidence disease and also sort of related diseases such as stroke. Navine: Sure. I think genetic risk scores are useful when the effects of each individual variant are very low. Compiling comprehensive genetic risk score may add incremental value, and of course being able to predict the onset of atrial fibrillation is very valuable for many patients, as it's a common cardiovascular condition. Hopefully, this will be refined as we move forward. Jane: Absolutely. Actually, the second paper was sort of a similar application. This paper is called Common Genetic Variant Risk Scores Associated with Drug Induced QT Prolongation and Torsade de Pointes Risk. The authors here were David Strauss and Christopher Newton-Cheh and colleagues. They generated a genetic risk score variants that have been associated with QT intervals through sort of various genome [inaudible 00:27:54] association studies and then they did genetic analysis in a relatively small number of subjects, 22 subjects, but they looked at the association between this genetic risk score and the drug induced QT prolongation. They found that it actually explained quite a significant proportion of the variability in drug induced QT prolongation and it was a significant predictor of drug induced Torsade De Pointes. In this case, compared to the first paper where it had a relatively modest effect, they actually saw quite a good effect here where the addition of the genetic risk score was able to predict the reaction to the drugs. Navine: Yeah, Jane. I think as genetic information for each individual patient is going to be increasingly available, as whole genome sequencing or whole [inaudible 00:28:52] sequencing or even doing [inaudible 00:28:54], the costs seem to be going down. If patients have a digenetic profile available, then compiling such genetic risk scores and then being able to apply them for individual situations would make sense. Then I think it could be more widely clinically applicable because people should realize getting genetic testing is just not getting genetic testing but it's a lifetime of information that's available as we are able to use this genetic information in various clinical conditions as we are seeing in these two papers. Jane: Absolutely and it actually relates back to the AHA statement that we highlighted in this episode where genetic literacy is so important. It emphasizes the fact that practitioners and healthcare providers need to be aware of genetic testing an be aware of the potential that it has so that when genetic data is available for patients it can be used throughout the whole lifetime of that patient. Navine: That's great, Jane. I found an interesting paper that was published in this month, April 2017 Circulation Cardiovascular Genetics. It's volume 10 and it's titled Prevalence and Clinical Implications of Double Mutations in Hypertrophic Cardiomyopathy. The first author is Dana Fourey and the senior author is Arnon Adle. Essentially, what this study did was looked at all the hypertrophic cardiomyopathy in gene panel results that were available in 1,411 patients over a 12 year period and try to discern how many of these patients were genotype positive. It turns out that 19% of these patients, or 272 of the 1411, had pathogenic or likely pathogenic variance. The purpose of this paper was to see how many of these patients have so-called double mutations because having two pathogenic or likely pathogenic mutations in earlier studies have shown an earlier disease onset, more severe left ventricle hypertrophy, higher prevalence of advanced heart failure and increased risk of sudden cardiac death. They wanted to see if this was true in this large cohort of patients. It turns out that actually just 1.8% of that total population, or 25 patients, had such double mutations; meaning, two likely pathogenic or pathogenic mutations. Fairly small number of the total population. What was interesting was as they applied the latest American College of Medical Genetics and Genomics criteria, and remember this was done over a 12 year period, and what they decided to do was look at all these 25 variants and apply the latest criteria and see after this stringent overview whether these likely pathogenic or pathogenic variants held up. It turns out that of the 25, only one genotype actually held up to these criteria. Only one patient had these double mutations that were pathogenic or likely pathogenic, so 0.07% of the total population. The bottom line is, though it sounds interesting that if people have two likely pathogenic or pathogenic mutations they should theoretically have a worse prognosis and more severe disease, the reality is that this is unusual, and furthermore, when they compared these patients who had double mutations with those who had single mutations, they found no difference in these high risk features or premature death. It turns out that our knowledge is still evolving regarding having double mutations in hypertrophic cardiomyopathy. There's a nice accompanying editorial in Circulation Genetics April issue of this year if people want to read further into this article. Jane: It sounds really interesting. I'm thinking that that is a little related to the other paper that I wanted to talk about, which is not specifically cardiovascular related but I think they used an interesting approach that could be applied to cardiovascular conditions. The first Author is [inaudible 00:33:56] Cummings, last author Daniel MacArthur and this was published this month in Science Translational Medicine the 19th of April. The title is Improving Genetic Diagnosis in Mendelian Disease With Transcriptome Sequencing. What they did was they took muscle samples that had been collected from patients with a variety of rare mendelian conditions such as muscular dystrophies and myopathies. They decided to do RNA sequencing in these samples. These samples were from subjects and families that had previously been very difficult to diagnose. A lot of these subjects had already been subjected to whole exome sequencing or whole genome sequencing, and in many cases, they had been unable to find the [inaudible 00:34:43] mutation. They sequenced the RNA from the muscle and they compared it to control muscle RNA from [inaudible 00:34:53]. [inaudible 00:34:54] contains RNA data from hundreds of different individuals with healthy controls and they were able to filter the data from [inaudible 00:35:01] to get high quality RNA samples matched to the patient's age and BMI to some degree. They then compared the sequences to see if they could find aberrant splice variation or aberrant expression in the RNA samples from the patient samples compared with the controlled. They actually were able to find a lot of additional interesting causal mutations that were able to explain the diagnosis in subjects who were previously undiagnosed. Actually, in this sample of very challenging rare cases, they had an overall diagnosis rate of 35%. By identifying sort of aberrant splice patterns in these patient samples, they identified multiple causal variants that were not able to be identified through the usual means through whole genome sequencing or whole exome sequencing. They actually found 17 families where they were able to make a diagnosis where there had previously been none. Although this is in different conditions, not cardiovascular, but I think it highlights how sometimes using a different approach, for example doing transcriptome instead of genomic profiling in the disease relevant sample can give really interesting insight that you wouldn't get just from looking at the DNA sequence. Navine: That's a fascinating approach. This is more like a genotype transcriptome correlative study after the transcriptome has been further refined based on so-called normal transcriptome and this way they were able to identify the functional significance of certain genetic variants based on what the transcriptome looks like in disease states. Jane: Yeah, absolutely. They were able to sort of actually link variants of unknown significance with the actual transcriptomic pattern and then highlight the variants that actually did have a causal effect on gene transcription. Navine: Thanks for pointing that out, Jane. It could be easily applicable to cardiovascular disease. It'll be interesting to see if papers come out based on this study design. Jane: Yeah. I think so. Navine: All right. We look forward to reviewing some more exciting papers next month. We'll be well into summer soon. Jane: We will. Great. Well, thank you, Navine. Navine: Thank you. Jane: That's all for this month. Thanks to Rick Andreasen at the Mayo Clinic Media Support Services for production assistance. Thanks, everyone, for listening. We look forward to bringing you another episode of Getting Personal Omics of the Heart next month.
Jane Ferguson: Hi, everyone. Welcome to episode six of our podcast. I'm Jane Ferguson, the current chair of the Professional Education and Publications Committee of the Functional Genomics and Translational Biology Council of the American Heart Association. It's July as we're recording this, so hopefully all you listeners in the Northern Hemisphere are enjoying the summer and taking a break to catch up on your podcast queue, maybe while relaxing at the beach or while navigating the twists and turns of the airport security line. In honor of summer, we're doing something a little different this month and featuring a bite-sized podcast with some research about how your vacation plans might be affecting your heart disease risk. For all our friends in the Southern Hemisphere, I'm sorry that this may be less relevant to you right now, but hopefully you're having a nice winter and enjoying the ability to go outside without sweating. On to our topic, let's talk about the defining feature of summer, sunlight. Humans synthesize vitamin D in response to sun exposure, and vitamin D deficiency can be associated with multiple adverse health consequences, particularly on bone health. However, there have also been reports of association between vitamin D and cardiovascular health. Prompted by observations that cardiovascular events peak during winter months and follow a geographical gradient with higher event rates at higher latitudes, the hypothesis was put forward in the early 1980s that CVD events are mediated by UV exposure through modulation of vitamin D status. This has been supported by a number of different strands of evidence. Large-scale meta-analyses of population data have found that low levels of circulating vitamin D, as estimated from measurements of serum 25-hydroxy vitamin D, are associated with increased risk of all-cause mortality and with increased risk of cardiovascular events and mortality. As summarized in an article from earlier this month in PLOS ONE, by Lars Rejnmark and Rolph Jorde, meta-analyses of randomized clinical trials have found a beneficial effect of vitamin D supplementation on blood pressure, depression, respiratory tract infections, and mortality. However, most find no beneficial effects, including no effects on CVD or diabetes. Some key limitations of these studies were that they often included a relatively small number of subjects, were conducted in individuals who were not vitamin D deficient, or used relatively low levels of vitamin D supplementation. What was lacking in the field until recently was a large-scale, randomized trial to definitively address whether increasing vitamin D levels in the general population would have a protective effect on cardiovascular health. The results of such a large-scale clinical trial of vitamin D supplementation were recently published in the June 2017 issue of JAMA Cardiology. The first and last authors were Robert Scraggs from the University of Auckland and Carlos Camargo from Harvard Medical School. They recruited over 5,000 individuals aged 50 to 84 for monthly supplementation with a hundred thousand international units of vitamin D compared with placebo control. This dose is sufficient to maintain serum 25-hydroxy vitamin D above 35 nanograms per mil. The study was continued for around three years, and events were ascertained from ICD-10 codes. While baseline 25-hydroxy vitamin D levels were inversely associated with CVD risk during follow-up, there was no significant difference in CVD events between the supplementation and placebo group. There were some limitations to this study, including a lower than expected event rate, a median follow-up time of only 3.3 years, and the study was not powered to analyze effects in subgroups of individuals with vitamin D deficiency. However, overall, this study adds to the evidence against a benefit for large-scale vitamin D supplementation. Another recent clinical trial of vitamin D and calcium supplementation published in JAMA in March of this year by Joan Lappe and Sharon McDonnell found no statistically significant effect on cancer incidents in a four-year, double-blind, placebo-controlled, population-based, randomized clinical trial in over 2,000 healthy, post-menopausal women, although there did appear to be a nonsignificant trend towards lower incidents of cancers in the supplemented group. Gina Kolata of The New York Times wrote a feature on vitamin D back in April of this year highlighting the recommendation to use a cutoff of 30 nanograms per mil to define low vitamin D status has resulted in large numbers of individuals being designated as vitamin D deficient. While levels below 30 nanograms per mil have previously been shown to be associated with diverse adverse health outcomes, causal inference, or evidence for a protective effect of supplementation, remains lacking. Particularly in light of the recent clinical trials showing null effects of vitamin D supplementation, the benefits of increasing serum 25-hydroxy vitamin D through supplementation remain unclear. There may be an important role for genetics in dissecting the link between vitamin D and outcomes. As reviewed in the British Journal of Cancer in March of this year by Peter Vaughan-Shaw and Lina Zgaga, genetic polymorphisms affecting vitamin D metabolism are associated with cancer outcomes. It is possible that vitamin D supplementation may have a protective effect only in individuals with a particular genotype. However, this remains to be tested. However, what none of these studies manages to resolve is whether sun exposure itself has any benefits. Perhaps there is something specific about the process of making vitamin D directly from UV exposure that confers protection. Or, perhaps there are other benefits of direct exposure to sunlight independent of the vitamin D synthetic pathway that we do not yet fully understand. Either way, enjoying a little time in the sun this summer may have some benefits, unless you get sunburned. So, please take advice from the dermatologists and avoid prolonged exposure, seek shade from the midday sun, cover up, and use sunscreen. Thanks for listening to this bite-sized episode. As always, the links to the papers featured in this episode are posted on fgtbcouncil.wordpress.com. We'll be back with more next month.
Jane Ferguson: Hi everyone. Welcome to episode seven of Getting Personal, -Omics of the Heart. I'm Jane Ferguson, an assistant professor of medicine at Vanderbilt University Medical Center and the chair of the Publications and Professional Education Committee of the Functional Genomics and Translational Biology Council of the American Heart Association. This month I'm particularly excited to announce a new venture. We have teamed up with the journal, Circulation: Cardiovascular Genetics to bring you this and future podcasts. CircGen publishes a lot of the most compelling research in cardiovascular genetics and genomics and precision medicine in cardiometabolic disease. We've already featured a lot of the research in previous episodes of the podcast. With this new collaboration, you can look forward to even more in-depth features of the newest research published in Circulation: Cardiovascular Genetics. This month, Anwar Chahal, a cardiology fellow at the Mayo Clinic, talked to Calum MacRae, the Chief of Cardiology at the Brigham Women's Hospital in Boston. The interview covered a variety of topics and we couldn't fit everything into this half-hour podcast. What you will hear in this episode is a discussion related to a recent publication by Dr. MacRae and colleague Aaron Aday in Circulation published in July 2017 entitled Genomic Medicine in Cardiovascular Fellowship Training. Dr. MacRae expands on the topic, How to Train Clinicians to Deal with Advances in Genomic Medicine and What we Can Do to Improve Implementation of Knowledge from Genetics and Genomics to Helping Patients with Cardiovascular Diseases. If you'd like to hear more from the interview, including discussion of Dr. MacRae's bold One Brave Idea project, and to hear more pearls of wisdom and career advice from Dr. MacRae, you can download the full interview in the special hour-long podcast. First, I do want to highlight one recent paper from the Functional Genomics and Translational Biology Council which was published in the June 2017 issue of Circulation: Cardiovascular Genetics. This clinical genomics paper was published by Laura Zahavich, Sarah Bowdin and Seema Mital, all from the Hospital for Sick Children in Toronto. The paper is entitled Use of Clinical Exome Sequencing in Isolated Congenital Heart Disease and describes the case of an infant with congenital heart disease where a pathogenic mutation in the notch one gene was identified through whole exome sequencing. The paper highlights the utility of whole exome sequencing when candidate gene panels are negative, allowing for increased understanding of causality and the ability to make risk predictions for future offspring. At the same time, this approach reinforces the importance of well-trained clinical personnel including genetic counseling, to appropriately interpret and disseminate findings from whole exome sequencing. A little aside, in case you are not aware of this, Circulation: Cardiovascular Genetics has a really nice feature on their website where you can apply filters to see specific types of publications. From the toolbar along the top of the homepage, you can go to Browse Features and then you can select Options from the dropdown menu, so if you click on Clinical Genomics Cases, for example, you will see all of the genomic case reports, which may be of particular interest to this audience. Dr Anwar Chahal: My name's Dr. Anwar Chahal. I am a cardiology fellow in training from London, UK, and I am doing my research fellowship here at the Mayo Clinic. I'm very honored and delighted to have our guest, Dr. Calum MacRae, so you are the Chief of Cardiovascular Medicine. You are a MD PhD by training and you are associate professor at Harvard Medical School and your expertise amongst many other things, internal medicine, cardiovascular diseases, but in particular inherited cardiovascular conditions. Is there anything else that you would add to that? Dr Calum MacRae: I'm a big fan of generalism and I'm quite interested in cardiovascular involvement in systemic disease as well, largely as a means of keeping myself abreast with the biological mechanisms in every system that seems to be relevant to cardiovascular disease. Dr Anwar Chahal: I think training across the world has increasingly recognized the importance of genetics and genomics, but I just want to share one little anecdote. My wife's a primary care physician and I was visiting the GP practice where she works and she'd mentioned that I had an interest in genetics and genomics and one of the partners came out with one of these reports that a patient had sent their sample to a private company, got this analyzed, brought it into the clinic appointment, and asked for an interpretation. The GP partner said to me, "I've absolutely no idea what any of these numbers, values, et cetera mean. I actually am looking forward to my retirement because I really don't want to have to cover all of this. Can you help me with it?" I sort of remember hearing Dr. [inaudible 00:05:48] talk here at Mayo Clinic, who's really pushed forward pharmacogenomics and he's been arguing for quite some time, as I've heard you say as well, that genomics and genetics is just going to be a part of the medical record in the same way that hemoglobin or a chest x-ray is and people better catch on because it's here, it's available, commercially people can send their samples directly without their doctor's involvement and then it's trying to make sense of all of that. I think as a community research and clinical we have to take this very seriously and I'd be grateful for your insights on that and then if you could then tell us what would be the best way for the up and coming generation and for programs to incorporate that into their training. Dr Calum MacRae: I think you're right, there is a general tendency in the public domain to test a variety of different genotypes, and in many instances I think the key elements are how do we as a profession conceive of these tests? I think one of the things that we forget perhaps at our peril is that many of these things are problems that we've encountered before. There's a natural cycle of different tests in medicine where they start off in the academic medical centers, they propagate into the periphery, and then eventually they're assimilated as part of internal medicine. I think the scale of genomics is obviously somewhat broader than many individuals have seen in the types of data that they deal with on a day-to-day basis, but I think that's something that's happening in everybody's life, and every aspect of your life, you have many more channels to deal with, you have many more choices in the supermarket to deal with. I don't see this as a sort of existential challenge to medicine; quite the opposite. In my experience, the core things that we need to remember is that DNA is no different from any other assay, except for the fact that it's relatively straightforward to do DNA diagnostics. It's technically not as sensitive a set of biochemical issues as are many other assays that we use in day-to-day clinical practice. The other thing that I think is perhaps a key element is that I said a few minutes ago, it's a [inaudible 00:08:35] dataset and it's stable for your whole life. You only need to have it tested once. It's sort of invert to the typical diagnostic paradigm, so instead of a primary test being interpreted in the context of an ongoing clinical event, the test may have been present for four decades and the results will evolve over time in light of the changing phenotype or some new information in respect to that genotype. What I've actually looked on genomics as is almost an organizing principle for the way that you build care. In fact, I see quite frequently, we probably now have an average one or two new patients a month in my clinic who bring their entire full genome with them, either an exome or a whole genome. We've begun to really get to know quite well how to manage patients. Obviously they're a select group of patients but one of the things that I find is that patients are really quite astute in understanding that genotype and phenotype are not deterministic relationships. What you have to do is always interpret these things in context of a probabilistic understanding. Most patients I think when they're told this understand that we're going to learn much more about genomics going forward than we will ever imagine that we could know at the present. That will involve lots of different things. It will involve new ways of displaying data, new ways of thinking about the data in the clinical context. I actually think one of the most interesting things about genomics and to be honest any assay is that they rarely reach any form of maturity until they are used in the clinic, until they are actually used in implementation. For example, many genetic tests at the moment don't change therapy and they don't change outcomes, but partly that's because they've never been studied in that context, and one of the things that I think [inaudible 00:10:45] has to be really congratulated for is his focus on pharmacogenomics as being one of the early areas in which this will really move forward. I believe that by immersing ourselves in it, by actually trying it within the clinic where we're going to learn much more, and part of that gets back to the original topic that we spoke about, which is phenotype. The only way to really begin to understand collection of phenotype is if you do it in the context of existing genotype I think. As we move into new phenotypic areas, we're not going to be able to test everything and everybody. I think there the genome will end up being an important framework, lifelong framework for the management of a patient's diagnosis, prognostication and then therapy, potentially in that order. I think you need a whole different set of skills, you need a whole different set of technologies, but most importantly you need information that you can interpret in the context of the person in front of you. Until you can make mechanistically important insights with one person, it's going to be very difficult for genomics to really change medical care. That's something I think we should be focusing on. I think we've tended to have an associate of strategy for genetics. We haven't driven it into the clinic. As we drive tests into the clinic, whether it's troponin T or whatever, you begin to understand much better how to use them, although sometimes that can also go in quite extreme directions that you may not necessarily anticipate. I mean, troponin originally was a stratification tool for acute coronary symptoms, and now it's virtually a diagnosis in its own right. I think you'll see that tendency revert over time as people begin to understand the biology of troponin, of isoform switching in peripheral tissues of the way in which troponin may represent very different disease biologies. At the moment, it seems like it's a very simple and straightforward yes/no type of test. There's no such thing in medicine, and I think that's what we're learning about genomics and so instead of conceiving it as a series of 10 to the nine yes/no tests, we're going to end up with a very different vision and view of how it can be implemented to clinical practice. That can only come from having clinicians and geneticists work together on this. In fact, one of the things that we've been doing in the partners environment with some of our colleagues, and I have NIH funding to do this with Heidi [Ream 00:13:31], with Sandy [Aronson 00:13:34] and with Sean Murphy is to think about how we display data, but also how we collect information in light of that genomic data that helps in an iterative way in the learning fashion inform genotype phenotype relationships in a much more probabilistic manner than we have done to date. There are lots of efforts and that's great, that just happens to be one that I'm involved in, but I think it's a generalizable approach that you're going to see moving into the clinic in the next few years. From the standpoint of training, I think what you want to do is get exposure to all types of genetic information so you understand common [alleles 00:14:15], rare alleles, genomics and individual panels and I think the best way of doing that is to have it be part of training programs. In fact, with one of my junior colleagues, Dr. Aaron Aday, we recently wrote a short piece highlighting how important it will be for all of us to come together to think about how do we start to introduce the concepts of genomics into standard clinical training programs, and that's something we're working on fairly avidly at the Brigham and I'm sure there are, I know there are efforts at many other institutions to do similar things. Dr Anwar Chahal: That article is published in Circulation in July of this year if anybody wants to download that. I think if we talked to clinical trainees and asked them what are their concerns about training, as you know training can be very long in cardiology, which is a procedurally based specialty whether or not you become an invasive proceduralist at the end of it, there is that component at the beginning, and do you think a standard, in the US, a standard three-year program with two years of clinical and one year of research can incorporate that at a sound enough level to allow somebody to practice or do you think we're going to look at increasingly a one-year or a six-month sort of add-on fellowship for those interested more on the inherited side or more on the genomic side? I, like yourself, trained in London and the training programs are longer in the UK. It was probably six years when you were there. It shortened to five, and now increasingly it's going to become six and maybe even more with a general fellowship for five years and then a super advanced fellowship and inherited cardiovascular conditions certainly there has become a module that is encouraged for people to take and then become somewhat certified in inherited cardiovascular conditions. What do you think there in terms of incorporating all of that as well as learning basics of eco and device therapy and catheterization? What are your thoughts there? Dr Calum MacRae: Again, I look at this as a spectrum. I think there's a trajectory for all of these types of innovation and knowledge and it starts off being super specialized, it goes into a more general location, and then eventually it's an integral part of everybody's clinical practice. I do think that what you're going to see is rather than, and this is already I think the case in many elements of medicine, medicine has already exceeded the knowledge base even when I was training by probably a long order in terms of the complexity and extent of content, not that I trained that long ago. One of the core elements I think that we're seeing is that we need to move medicine from what I believe has become somewhat de-professionalized, say, to one where you're focusing on, not on the actual core knowledge that you bring with you to the table, but actually the way in which you integrate knowledge. I think the focus of training is going to change somewhat. It has had to change in other fields. Medicine I think for a long time favored that sort of single, comprehensive approach in one mind. Medicine is going to become more of a team sport and it's also going to become more of a knowledge integrator profession than it has been for some time. It's interesting, when medicine started there was so little knowledge that you really had to have almost every physician be an experimentalist using [inaudible 00:18:37] experiments in front of them. I think the way that I see medicine evolving is that as the knowledge base and the rigor of that knowledge base improves, many of the things that we think of as professional activity today will actually devolve to primary care, and to be honest into the community. There are many things where the rigor of the underlying data are such that there's no reason for a provider to be involved, for a licensed provider to be involved. We allow our patients to install their own wireless networks without a technician. I'm sure most of them can look after their own lipids pretty effectively if they were given the right information. A lot of stuff will begin to move in that direction. As that happens, I think the way in which information is displayed, the way in which data are collected and the workflow around integrating information will change. That doesn't get past the point that you brought up, which is that that will probably take a couple decades and in the interim, I think people are going to end up training in modules of sub-specialties, but I think one of the things that I sometimes like to ask myself is, "What's the end game? Where is this going to end up? Can we build systems that train directly for that end game rather than going through these intermediate steps?" I think that's something where I think we tried in the short piece that we wrote in Circulation to argue that everybody should have some exposure and that that exposure can change over time. We should be equipping people not to know genomics but to be able to learn how genomics is impacting their patients for the next 50 years. That model of professional training is actually the one that really was the dominant model until maybe a hundred years ago, and then the reasons for it don't quite seem obvious to me, at least at the moment. We sort of tended to slowly move to more of a learned knowledge base that was then applied. Physicians sort of steadily got to the point where we're now data entry clerks. The actual amount of professional and intellectual engagement has I think slowly diminished in many medical sub-specialties and medical specialties. The opportunity that genomics and other advancements in technology in medicine bring is the chance to I think re-professionalize ourselves to move from just simply defining ourselves in terms of the knowledge base that we each bring to the table, but defining ourselves rather in terms of how we put the knowledge together around individual problems and individual patients, a very much more patient-centered, biological approach than perhaps we've had over the last couple of decades. I think these are, I'm obviously stating a lot of this in somewhat in extremes, but I think these are general trends that you see in medicine. They've happened in other fields as well and people have overcome them. It's usually a function of changing the workflow itself, of changing the way in which the information ends up in the professional's hands and how you collect the data that you use then to interpret the existing knowledge. That I believe we haven't really reworked probably since Osler's time. It is amazing that we still have workflow, I mean it's amazing in lots of ways. It's an amazing tradition. It is quite interesting that we still have workflow that's probably largely dependent on what Osler liked to do when he was growing up, in terms of the times of day that he got up and his workflow. That's sort of instantiated in many ways in everything that we do. Nothing entirely wrong with it, but there's a lot happened since then that we haven't really changed. Medicine is not yet in many instances a 24/7 profession, and yet most other things that have much less in the way of impact in society are already 24/7 professions in many settings. I think you're going to see a lot of demographic changes in medicine come from the advent of technology in other industries. I think those will all transform the way that we imagine training in medicine. Along the same sort of timeline as some of the traditional approaches that you described, building out a training module and then having a subgroup of people do six months or a year of extra training. I see that as a short-term solution. I think ultimately longer term solutions are changing the whole workflow of medicine. Dr Anwar Chahal: What have you done in your own program at the Brigham to introduce genomic medicine training for fellows? Dr Calum MacRae: We are building out, obviously we have a fairly large cardiovascular genetics clinic, I think probably the largest in the world. We have now seven, soon to be eight providers working only and wholly in cardiovascular genetics. We therefore have the ability to have our fellows rotate through our genetics clinic. We have in-patient and out-patient genetic services and we also obviously involve our fellows in a lot of the academic pursuits going on in both our genetics and genomics programs in the cardiovascular clinics, as we do our colleagues who are no longer in training. We have regular, in our clinical conference slot we have several times a year, we have a genetics component, and then what we have also is an integrated training program with clinicians and pathologists that is really bringing the individuals who are understanding the technical aspects of the genetic testing with the individual sort of learning and understanding the clinical aspects of that testing. We imagine over time that this will evolve into potentially the type of specialist module that you described but also into a fixture that goes all the way through our two-year clinical training program. We've sort of taken the point of view that we probably need to do a bit of both. We need to, given what I said in the last few minutes, that we need to take a thread that recognizes a short-term and intermediate term need for specialization but also recognizes that we have to equip every one of our trainees and every one of our physicians with the ability to begin to learn the underlying science of genomics and the underlying approaches to using genomics in every aspect of clinical cardiology. We're doing both of those things and have active efforts in both. Dr Anwar Chahal: You mentioned integration with pathologists but for our colleagues who are not clinicians, what about the research angle and the scientists when they're in training, is that integrated so that we are getting this meeting of minds that is essential? Dr Calum MacRae: Absolutely, in fact we, thanks to a variety of efforts at Brigham Women's we have now at least three separate venues in which this occurs. I mentioned cardiovascular genetic clinic. We also have a genomic medicine clinic, which I'm one of the clinical codirectors for, where we actually have cases of [inaudible 00:26:45] through routine clinical care that seems as if they would benefit from whole genome or whole exome sequencing, and then we have a weekly conference that's actually led by Dick [Mass 00:26:58] and Shamil [Sonaya 00:27:01], two of our genetics colleagues and takes in specialists from all throughout medicine as well as scientists from the entire Harvard Medical School environment, and so we bring everybody together around mechanistically solving individual clinical cases. The third venue is one that's part of a national network, the undiagnosed diseases network. We're one of the sites on the national, the NIH-funded UDN network. There again one of the themes is identifying individuals or families who would benefit from both rigorous genomic analyses as well as much deeper phenotyping. That's been a program that I think has been very exciting and one that we again have learned a huge amount from in terms of how do you begin to build the infrastructure that brings not just the first clinician to see the patient, but somebody who, a whole team of people who understand and can evaluate all the biological aspects that are relevant in that patient. Then also brings to bear the scientific expertise that you might need in order to make a mechanistic connection between genotype and phenotype in that one individual, and some of that involves animal modeling. In cancer for example there's a concept that has emerged over the last two to three years of what's called co-clinical modeling that once you've identified some of the genomic features it allows you to begin to model in an animal in parallel with the trajectory of a patient- Dr Anwar Chahal: [inaudible 00:28:40] as some people call them. Dr Calum MacRae: Exactly. Creating an avatar. In many instances that's an avatar that includes multiple different disease models. We've begun to do that in the cardiovascular space. I think obviously it's early days yet, but I think there are lessons to be learned about how you build the types of infrastructure that allow people to move beyond this state where a patient's outcome is dependent on him seeing the right doctor on the right day at the right time. There are actually systems that funnel the patients into the right venue based on objective criteria at every stage. I think that's the type of re-organization, re-imagination of the medical system that we need. We sort of duplicate things in lots of different areas and you're still dependent on hitting the right specialist at the right day at the right time, or not seeing a specialist, seeing a generalist on the right day at the right time, who's able to put everything together, or even hitting somebody who has the time to listen to your story in a way that helps you identify the exposure or the genetic basis of your condition. If we recreate the professional environment that I talked about earlier, I think, in ways that are both traditional and novel at the same time, I think we'll do ourselves a great service and build a platform that lets all of the technologies, including genomics that we've talked about today, begin to impact patients in a real way on a regular basis. Dr Anwar Chahal: Thank you for that Dr. Calum MacRae for giving up your precious time and sharing your thoughts and insights and experience. Dr Calum MacRae: Thank you for your time and I've enjoyed talking to you. Dr Anwar Chahal: Thank you Dr. MacRae.
Jane Ferguson: Hello, and welcome to episode two of "Getting Personal: Omics of the Heart". I'm Jane Ferguson, an Assistant Professor of Medicine at Vanderbilt University Medical Center. This Podcast is brought to you by the Functional Genomics and Translational Biology Council of the American Heart Association. If you're a current or prospective member of the American Heart Association but not yet affiliated with our council, I do encourage you to join us. FGTB is a vibrant council with a diverse membership spanning disciplines from basic research to clinical practice, with shared interests in genomics, precision medicine and translational research. You can find out more by going to the AHA professional website at professional.heart.org and selecting FGTB from the list of scientific councils. If you're listening to this, you've obviously already figured out a way to access this Podcast. We do have several convenient options to make sure you never miss a new episode. You can stream each episode and find additional information on links to articles on the Podcast website fgtbcouncil.wordpress.com. You can also subscribe to the Podcast on iTunes or if you are an Android user, you can subscribe via Google Play. Just search for "Getting Personal: Omics of the Heart" and click, Subscribe. In this episode, Kiran Musunuru talks to Erik Ingelsson about research from his group on epigenetic patterns in blood and how these relate to coronary heart disease, which was published in the February 2017 issue of "Circulation: Cardiovascular Genetics". We highlight a recent AHA Science Advisory on merging electronic health record data and genomics, and Naveen Pereira and I discuss precision medicine and whether it can live up to the hype. Kiran Musunuru: Hello. This is Kiran Musunuru. I'm on the faculty at University of Pennsylvania and it's my pleasure to represent the Functional Genomics and Translational Biology Council of the American Heart Association. Today I have the privilege of interviewing Dr. Erik Ingelsson who is Professor of Medicine in the Division of Cardiology at Stanford University School of Medicine. We're going to be discussing a very nice paper on which he is senior author that was published last month in "Circulation: Cardiovascular Genetics" titled "Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies". It's all right there in the title. Erik, welcome. Erik Ingelsson: Thanks. Kiran Musunuru: It's a pleasure to have you. Maybe you can say a word or two to introduce yourself and your research interests. Erik Ingelsson: Yeah, it's a pleasure to be on. Yes, as you said I'm a professor of Medicine at Stanford, an MD, PhD trained really in epidemiology but started to do genetics about 10 years ago. I've been most of my career in Sweden but moved to Stanford now about one and a half year ago. I'm doing broadly studies within omics and molecular epidemiology but also have a translational part where I do [inaudible 00:03:29] and model systems. Kiran Musunuru: That's great. To the subject at hand, so I think we all appreciate how, with the completion of the Human Genome Project about 15 years ago now, genetics has really taken off. What's interesting is, over the last few years, there's been a bit of a shift in focus from genetics to the layer of regulation that lies right above genetics and that's epigenetics, so modifications of DNA and the proteins that are bound to DNA and how this interacts with genetic expression and then has consequences in terms of clinical traits and diseases. What caught my eye about your study is that you're actually looking at epigenetic regulation of gene expression but not in a very traditional, one locus at a time or one gene at a time fashion, but really in a genome-wide fashion. Whereas, starting in 2005, we started to see genome-wide association studies. Now we're starting to see, just over the last few years, epigenome-wide association studies. Personally speaking, one of my research interests is lipid traits. I thought it was very nice how you were able to apply an epigenome-wide association study to lipid traits and actually find some very interesting things. Why don't I start by asking you simply describe the main goals of your study. Erik Ingelsson: As you've already referred to, we wanted to look at variation in DNA methylation, which is one of the ways to look at epigenetics. I think either it's the most common way to look at epigenetics, at least if you want to do it genome-wide. We looked at variation in DNA methylation in relation to circulating lipid levels, and we did this through this epigenome-wide study and in whole blood derived DNA. We did it with about 2,300 individuals from the Framingham Heart Study and from the PIVUS cohort, and then we had an independent external replication in about 2,000 additional individuals. In addition to looking at these DNA methylation associations with lipids, we also wanted to look at these DNA methylation patterns in relation to incident coronary heart disease. We also wanted to integrate all of this with genetic variation, gene expression and also actually with metabolites through metabolomics. The whole idea here is trying to understand genomic regulatory mechanisms that link lipid measures to coronary heart disease risk. Kiran Musunuru: That's one thing I really liked about this paper, how you really took it all on. It wasn't just one particular type of omics analysis. It started with epigenomics but then you really went the extra mile, I thought, to connect it to genetic variation, and then to disease, and to metabolomics and so it was very comprehensive that way. Why don't we discuss the actual findings. You actually found quite a bit in your analysis, didn't you? Erik Ingelsson: Yeah. I think some of it were already actually in the title. We did, as I said, several different layers of things. The first thing was really to look at methylation patterns. We looked at CpG sites across the whole genome, and we identified almost 200 such sites that were different lipid levels in the discovery but then going to the replication stage, we had a little bit more than 30 of them being replicated and 25 of them had never been reported in relation to lipids before. That's one layer, so it is new associations. A lot of the genes that were then enriched they were involved in lipids and amino acid metabolism so it makes a lot of sense biologically. There is the one example of an interesting finding there with ABCG1 that we perhaps can discuss a little bit later. Other larger things that we found was that there was a lot of cis-methylation quantitative triglycerides so that means that there were a lot of genetic variants that were associated with these methylation levels. In fact, actually, 64% of all of the CpG sites that we found, they also had genetic variance determining the level of the methylation. So quite large fraction being genetically determined. We also- Kiran Musunuru: That's actually quite interesting because typically when you hear it in the lay press or what not about epigenetics, they tend to equate epigenetics with more environmental influences. It's a simple dichotomy or simplistic dichotomy of your genes are what you're born with but then epigenetics is the way that environment actually modifies your genetics in ways. But what you're suggesting from your findings is that it's actually genetic variation itself that could be directly responsible for epigenomic variation, which then would have effects on gene expression. Erik Ingelsson: I agree. I think we're seeing a shift a little bit in this field. Again, my background is not really within that genetics field so I'm a little bit on the side here but what I see is that it's come more from an approach or focus really on inherited epigenetic changes so studies in animals, primarily, I guess a lot, but also in some human studies so more on that level to something that had been, as you mentioned, a lot of focus on environment causing methylation changes and now almost more into a focus of gene regulation and then gene expression and that focus. Perhaps the ENCODE project and the Epigenome Roadmap and those projects have moved this field a little bit towards more focus on gene regulation and gene expression and that's kind of a part, a linking variation to gene expression. I think we're seeing a shift a little bit in that field. Kiran Musunuru: That's very interesting. Can you give an example of a particular locus or particular gene where epigenetic regulation really seems to be playing an important role, not just with respect to lipids but even, perhaps, connecting to disease. I think you'd mentioned ABCG1 very briefly. Erik Ingelsson: That's actually a pretty interesting locus. It's been recorded in the past, as well, in relation to methylation but we linked it all together. Basically, we see this intronic variant here where the minor allele is associated with increased methylation at the CpG site in that 5 prime UTR region of this gene of ABCG1 and then so that minor allele leads to increased methylation. It also leads to decreased expression of ABCG1 in blood. I think that makes sense. Quite often in the past, people have recorded that increased methylation should decrease expression. As we see that, we also see an effect on triglyceride levels and HDL levels as well and, interestingly, also, on the risk of coronary heart disease. In addition, also, associations with several of the metabolites, so single myelins and[karomites 00:11:40] which have also been implicated in coronary heart disease in some prior studies. It all comes together quite nicely at this locus where you have a minor allele increasing methylation, decreasing expression, increasing triglyceride levels and increasing the risk of coronary heart disease along with increases in some of the metabolites that also have been linked to coronary heart disease. Kiran Musunuru: Wow. Fascinating. Erik Ingelsson: Yeah, I think it's pretty interesting, actually. We could link it all together in the study. Kiran Musunuru: That's very nice. Another aspect of this study that caught my attention is that you really did it in a fairly rigorous way. You had your discovery cohorts in which you did the initial screen or the initial association study, but then you also had replication cohorts where you were then able to go independently test your findings and then accrue more evidence or lack of evidence for replication in the ones for which there was evidence of replication, those are, obviously, much more stronger results. I expect that we have among our listeners trainees who might be interested in hearing more about how you were able to assemble so many different cohorts to be able to get this study done. Erik Ingelsson: I think that's an important question. I would say that it goes back a little bit to the development that we've seen in genomics in the past 10 years. People coming in from gene studies to GWAS realizing that you really need to work together both because the science is better but also just if you want to establish any robust findings that can be replicated, you need to combine the data. I think we've seen that for GWAS clearly, but I think we're starting to see that also for other [inaudible 00:13:28] approaches as we move forward. Because all of these approaches are prone to false-positives so if you just do your analysis in your own data, then you're more likely to report false-positives and you need replication. I think we're lagging behind a little bit for epigenomics and other omics methods, but we're truly starting to see this happening also in other omics fields. I think, in a sense, the field is prime for collaboration and then I'm talking about the broad, molecular epidemiologist field or the people having cohorts and this kind of data, they're all used to working together from the GWAS era and also realize the need for it. I think for that reason it's usually not that difficult to get people together. Then how do you do it practically? It's easier if you know people, of course, since before and that's probably more common nowadays than it would have been 15, 20 years ago because you always used to work with people in the GWAS era and you can even add a junior level set up these collaborations because you might have been involved in some other collaboration before and know some postdocs in some other labs, etc. That might be one way to go about but the other thing is also that you have an interest in a certain phenotype and then you reached out to people that you think have the data. You can know about either from other publications and other phenotypes or on the same phenotype or just by word of mouth you know it since you've met people at conferences, you've seen some poster on the same phenotype, etc. I would say that people, in general, are very open to collaborations, and I think we've seen that change and shift of the past 10 years. I think we see it now also for other omics methods, and I definitely do think that's the way forward. To report more robust findings, in general. Kiran Musunuru: In closing, I'd say that seeing your study and seeing the very nice results, it seemed very promising with respect to what we're going to find going forward and doing epigenetic studies. Do you see more of this happening in the near future? Maybe even what happened with GWAS where it just got increasingly larger and larger studies and finding more and more results as these studies became increasingly powered. Erik Ingelsson: Yeah, I think so. I think for epigenomics, as with some other omics, I think we will see the same development that we saw with GWAS, which is the people start to publish in relatively small settings with perhaps a few discovery cohorts, a few replication cohorts, and that parts happen kind of independently of each other. Then the next stage is you're grouping together and you're starting to involve other people as well and these consorts get larger and larger. I think the value of this data can be exponentially increased if you can actually combine it with other data sets. We've seen that in genomics. There's a large return on your investments by collaborating with other people. I definitely do see the same kind of development happening here, as well. Kiran Musunuru: Well, Erik, thank you so much. That's all the time we have for today but we greatly appreciate your taking the time out of your busy schedule to discuss with us this really nice paper that you and your colleagues published very recently. I would encourage all of our listeners to go take a look at the paper themselves. As I recall, this particular paper is open access so it should be freely available to anyone who is interested. Is that correct? Erik Ingelsson: Yes, it's an open access. And thanks, Kiran. It was a pleasure. Kiran Musunuru: Thank you very much. Jane Ferguson: An AHA Science Advisory from the FGTB Council published in 2016 focused on the challenges and the potentials in merging electronic health data with genomics data to advance cardiovascular research. Jennifer Hall, John Ryan and colleagues published this on behalf of the Functional Genomics and Translational Biology Council as well as the councils on clinical cardiology, epidemiology and prevention, quality of care and outcomes research and the stroke council. As electronic health records have become ubiquitous in medical practice, there is an opportunity to utilize existing stored data and add new types of data to the EHR to facilitate research through EHR-coupled biobanks and to improve patient care through the use of precision medicine approaches based on genomic and clinical data stored in a patient's record. While logistical and ethical considerations remain, this is an area with great promise. You can read more in the Science Advisory published in the March 2016 issue of "Circulation: Cardiovascular Genetics", which along with all the papers mentioned in this episode, are linked on the Podcast website at fgtbcouncil.wordpress.com This Podcast has the focus of precision medicine, and I saw an interesting back and forth in the JAMA comments section about the hype of precision medicine. I think even those of us who are fond of precision medicine would agree that there's probably a certain amount of hype surrounding it. There was this interesting opinion published in JAMA last October addressing the question of, will precision medicines really have an impact on population health? I think there is some important points that really to improve population health, there may be other options rather than precision medicine, which may be more focused on the individual or on certain subgroups, which may not actually raise the broad population's health. But then there was response to that published in JAMA in January, which was arguing against it. I thought it would be some interesting thing for us to talk about a little to see do we agree? Is this over-hyped? Or is precision medicine really something that could fundamentally change population and individual level of health in the future? Naveen Pereira: I agree. There seems to be a tension between precision medicine that stresses on the individual and using omic technology and molecular markers to determine individualistic response or characteristics and population health in general, which looks at population trends. Both of them in principle and philosophy appear to be deferring fields. I guess the question is how do we integrate both of them to improve overall, not only individual but large population health? Jane Ferguson: I think there's probably some disconnect maybe between what people think of as precision medicine and what sort of things it includes because I think our first thought could be that precision medicine is very much based in genetics and genetic risk scores, using genotype as a way to predict an individual's response to a drug or their risk of disease. I think maybe one of the things we have to think about with precision medicine is to encompass all of these additional omic technology. So, yes, genotype alone is unlikely to really affect population health on a broad scale, but when you add in gene expression and proteomic biomarkers, metabolomics and microbiomes, I think then we do start to get to a point where it's mathematically complex but it would theoretically be possible to predict risk and implement precision medicine approaches, even on a large-population scale. Naveen Pereira: Right. One of the things I've always wondered is should we move away from our traditional classification of disease? For example, hypertension. Is all hypertension the same? We know it's not, it's such a heterogeneous disease process. Are we still stuck in the 19th century where we think of hypertension as blood pressure? Should we move away from that? Should we integrate all this great input from omics technology and phenotype hypertension is a better disease process, which would, perhaps, improve outcomes. Jane Ferguson: I think that's a great point. Honestly, probably a lot of the challenge in this is just us in thinking about things differently. You're right. We're very used to thinking of hypertension and we recognize it, we treat it. But it really is just ... The underlying causes of hypertension in the individual may be very different and it may need very different treatments. I think a paradigm shift is probably needed in thinking about a lot of these complex diseases. Diabetes is another one where really that's the causes and then the way it progresses in different individuals is probably really distinct subtypes of disease rather than being one broad disease that we can classify as such. Naveen Pereira: Exactly. And that would enable, perhaps, more dramatic treatment effects, too. I keep thinking of the example in cystic fibrosis where the genetic mutation in the cystic fibrosis gene actually proved that a certain therapy for cystic fibrosis in those patients who carry that gene mutation had a dramatic response. It didn't take tens of thousands of patients to demonstrate that effect but it took several hundred patients. Jane Ferguson: That's a great point. I think if we're accurately substratifying individuals so that we really are looking at people who really do have the same underlying causes of disease, then I think we will have a lot more power to see effects in smaller numbers of people and we can move away from these huge GWAS of hundreds of thousands of people as being necessary to find effect. Naveen Pereira: In fact, what we could do is take some of the knowledge from precision medicine and apply it at a population level and, hence, perhaps what we need to do is integrate the two disciplines better and people need to speak to each other more often. What do you think, Jane? Jane Ferguson: Absolutely. I think that is key. We're used to thinking about our own little narrow field and focusing on that but I think integration and finding good ways for it. The humans to integrate and also to integrate the data mathematically, I think that will be key. I think that certainly caveats, I mean, these approaches may not find everything but I think there's definitely a lot of promise that has not yet been fully exploited. Naveen Pereira: Absolutely. Jane Ferguson: Last time we talked, we were talking about a paper that used gene expression profiling in CAD. I think you found a really interesting paper for us to talk about this month looking at gene expression profiling but in the setting of heart transplant and heart transplant rejection. Naveen Pereira: Yes, Jane. It's interesting to see increasing number of publications now looking at gene expression arrays and profiling for various disease states. In the March 7, 2017, issue of "Circulation", there was a very interesting paper looking at gene expression profiling and complementing the diagnosis of antibody-mediated heart rejection. Just as a background, the two types of heart rejection that heart transplant recipients can have, one, is cellular rejection which we're seeing now less often due to improvements in immunosuppression; the other type of rejection is antibody-mediated rejection most often caused by anti-HLA antibodies that are directed towards the donor or what we call as donor-specific antibodies. This paper, the first doctor is Alexandre Loupy and he is from INSERM Institute in Paris, France and the senior author is Philip Halloran who is from Edmonton, Canada. What they essentially did was look at 617 heart transplant patients from four French transplant centers. Out of these 617 recipients, there were 55 recipients who had antibody-mediated rejection. They did a case control study, the controls being 55 recipients who did not have antibody-mediated rejection. They analyzed 240 heart biopsies in total. Unfortunately, even in this modern era, we still perform heart biopsies traditionally through the internal jugular route and endomyocardial biopsies and these biopsies are then analyzed for features of antibody-mediated rejection. The International Society of Heart and Lung Transplant has standard definitions by consensus as to what is antibody-mediated rejection and their various features histopathologically and by immunostaining. We also use donor-specific antibody detection in the serum to finally make a diagnosis. What this group really did was analyze these heart biopsies by performing expression microarrays and they found a very distinctive pattern in patients who had antibody-mediated rejection by traditional criteria. The gold standard was the traditional criteria, and they used the gene expression pattern to correlate it with the gold standard. They found certain selective gene sets that they call antibody-mediated rejection gene sets. It involved transcripts of natural killer cells, endothelial cell activation, macrophages and interferon gamma. The area under the curve that they found using these gene expression patterns for these four gene sets was greater or equal to 0.8 which is quite good. This gene expression pattern was then validated in a separate cohort of patients from Edmonton, Canada. It's an interesting manuscript, which essentially looks at using gene expression profiling in addition to traditional histopathological determination for a relatively common type of rejection in heart transplant patients to consolidate the diagnosis and give insight into pathophysiology. But some of the questions that arise are we still submit patients to endomyocardial biopsies so this does not supplant the need to perform endomyocardial biopsies because this was looking at expression arrays within heart tissue. We are still struggling with the gold standard, the histological diagnosis of antibody-mediated rejection as to what it really means in patients, for example, who do not have dysfunction of the graft, or a low ejection fraction. Useful in many ways. I think it adds to the overall knowledge of this phenomena, but it may not change clinical practice significantly. Jane Ferguson: That's really interesting. It's exciting but, you're right, we are subjecting people to heart biopsies isn't necessarily going to be a good way to monitor rejection or be able to predict in advance who is going to suffer rejection versus not. I think it's definitely a very interesting study and I think, the fact that they discovered these genes that which were then validated, may give some additional insight into the underlying biology, which may help us develop new ways to start thinking about treating this unmitigating rejection. Naveen Pereira: Right and it would be interesting to see how this corresponds to peripheral blood gene expression and whether there's an early, noninvasive way of detecting rejection. I know the Stanford group in the past has looked at circulating DNA from the donor heart, analyzed by peripheral blood, the same thing that's done in efforts to its cancer detection to see if we can pick up rejection by just a blood draw instead of doing endomyocardial biopsies. Jane Ferguson: Yes, definitely. I wonder if this group collected any blood or is this something they may want to do in the future because I think that would be a really interesting addition to this study. Naveen Pereira: Absolutely. Jane Ferguson: Well, it's been great talking to you as always, Naveen, and we want to say special thank you to Rick [Andraysen 00:31:10] for the Mayo Clinic Media Support Services for helping us with this Podcast. Naveen Pereira: Always does a great job. Jane Ferguson: Absolutely. We'll thank everybody for listening and we'll look forward to being back with you next month with more topics related to precision medicine and getting personal with omics of the heart. Naveen Pereira: Lot of excitement next month, Jane. Thank you.
Jane Ferguson: Hello, and welcome to episode one of Getting Personal: Omics of the Heart, a podcast from the Functional Genomics and Translational Biology Council of the American Heart Association. I'm Jane Ferguson, the current chair of the FGTB Professional Education and Publications Committee. This monthly podcast will bring you up to date with the latest in genomics, other omics technologies, and precision medicine as they relate to cardiovascular and metabolic disease. In each episode, we'll give you an overview of some of the latest research to be published, and delve deeper into topics of particular interest. Whether you're a clinician, researcher, genetic counselor, or other healthcare or science professional, we hope these podcasts will be informative, and help you stay up to date with the latest developments in this exciting field. In this episode, my colleague Naveen Pereira talks to Amit Khera about his recent publication with Sek Kathiresan and colleagues in the New England Journal of Medicine entitled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease, and we highlight a recent AHA scientific statement on the use of genomics. But first, Naveen and I will give you a round up of some interesting papers from the past month. Naveen Pereira: So Jane, there was this really interesting paper in the American Journal of Medicine whether we can use gene expression signatures along with other clinical covariates to predict the presence or evaluate whether symptoms are suggestive of obstructive coronary artery disease. Jane Ferguson: Yes. This paper was published online on the 16th of December 2016. It comes from Joseph Ladapo, Mark Monane and colleagues. They carried out this study in 566 patients from the PRESET Registry, which enrolled stable, nonacute adults presenting with typical or atypical symptoms that were suggestive of obstructive coronary disease. What they did was calculate an age/sex/gene expression score, or ASGES score. They included gene expression, which they measured in a blood sample collected in a PAXgene Tube, and this score ranges from 1 to 40. They've previously validated this, and a score less than or equal to 15 indicates that a symptomatic patient is very unlikely to have obstructive coronary artery disease. The genes they measured include 23 genes that are selectively expressed in circulating neutrophils, NK cells, and B- and T-lymphocytes. Naveen Pereira: So really, this expression reflects inflammation, and the hypothesis being perhaps these inflammatory markers are very indicative of the presence of obstructive coronary artery disease, or plaque rupture I guess, huh? Jane Ferguson: Yes, exactly. What they actually found was that individuals with high scores were referred to cardiology or advanced cardiac testing at far greater rates, and then even of subjects with low scores who did undergo additional testing, none of them had any detectable abnormality. Then, in subjects with high scores who did undergo further testing, 14% had abnormal findings. So after a year of followup, 1.2% of patients with an ASGES score below 15 had an adverse event, compared to 4.5% of those with elevated scores. Naveen Pereira: So a fairly high negative predictive value, huh Jane? Jane Ferguson: Right. Right, exactly. Naveen Pereira: Did you find any limitations, Jane, in this study? Jane Ferguson: There were some. Well firstly, it's worth noting that the score itself, and this test, has been developed by CardioDx, and a number of authors on this manuscript are affiliated with CardioDx. In addition to that, they did not include a control group in this. That certainly is somewhat of a limitation, but the authors say that this is probably still useful, and it may have some clinical utility in guiding decision making for patients with obstructive CAD. However, whether or not this is actually true will probably require some additional testing. Naveen Pereira: So quite a foray into using this perhaps in the emergency room or in hospital. So I guess our audience should look out for this in the American Journal of Medicine, December 2016. Jane Ferguson: Yeah. Naveen Pereira: So there was another paper that we kind of thought was interesting, Jane, from the European Heart Journal. Jane Ferguson: Yes, exactly. This comes from Jozef Bartunek, and Andre Terzic, and their colleagues, and they were reporting this on behalf of the CHART Program. Naveen Pereira: So this was published on January 15, 2017. Jane Ferguson: Yeah. This was a prospective, randomized, double-blind, sham-controlled trial, which was the Congestive Heart Failure Cardiopoietic Regenerative Therapy, or CHART-1 trial. In this trial, they were aiming to test safety and efficacy of delivery of cardiopoietic cells. They recruited subjects who had symptomatic ischaemic heart failure, and they consented to bone marrow harvest and mesenchymal stem cell expansion. They ended up randomizing 315 subjects. They received cardiopoietic cells delivered endomyocardially by a retention catheter, or either a sham procedure. The outcome that they were looking at was a hierarchical score, which is assessed 39 weeks post-procedure. That score comprised all-cause mortality, the number of worsening heart failure events, the Minnesota Living with Heart Failure Questionnaire, a difference in the six minute walk test, change in left ventricular end-systolic volume, and change in left ventricular ejection fraction. So it was interesting. They found a neutral effect on the primary end point, but they did find some evidence of benefit in subgroup analyses, which were based on baseline heart failure severity. Naveen Pereira: But and this was not designed to show efficacy, because it was primarily a safety trial. Is that right, Jane? Jane Ferguson: Yes, exactly. Naveen Pereira: Right. Jane Ferguson: Overall, they found that there were no indications for concern regarding safety, so I think they've shown that certainly this is a technique that is safe and is well-tolerated, and I think it's really quite exciting. Future studies that are adequately powered, particularly looking at subgroups of individuals, may actually identify patient populations that would derive particular benefit from cardiopoietic cell therapy. Naveen Pereira: Fascinating, so it'll be interesting to see what the Phase III clinical trial will show. Overall, a new foray into regenerative medicine. Jane Ferguson: Yeah, yeah. Really interesting. Naveen Pereira: Hi everybody. My name is Naveen Pereira. I'm from the department of cardiovascular diseases at Mayo Clinic in Rochester, and on behalf of the Functional Genomics and Translational Biology Council of the American Heart Association it gives me great pleasure to interview Amit Khera. We are going to be discussing this very exciting paper that was published in The New England Journal of Medicine on November 13, 2016, titled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. Amit, welcome. We are so glad you could make it. We really appreciate you doing this for us. Amit Khera: Naveen, thank you so much for having me. It's a real pleasure. By way of introduction, as you said my name is Amit Khera, I recently joined as a staff cardiologist at Massachusetts General Hospital in Boston where I see both general cardiology patients and also work in the prevention center. But one of the things I've noticed is that many of us have heard a lot about precision medicine, and how we can incorporate genetics into some of our clinical decision making, or risk stratification. So I've really been working with Sek Kathiresan at both Mass General and the Broad Institute to get training in both genetics to complement some of the clinical medicine aspects in order to help us get at some of those questions. Naveen Pereira: Fantastic. Amit, what got you interested in genomics? Amit Khera: Sure. Well, you know for a complex disease like coronary artery disease, and risk of a heart attack, we've really known for a long time, like since the 1960s that there is a familiar pattern, meaning that if your brother or your father had a heart attack at a young age, your risk of having one is increased by almost a factor of two. It's really been only recently that the technology has allowed us to get at those questions, and really isolate the exact genetic determinant. So really in the last 10 years, we've been able to identify a large number of variants that influence an individual's risk of coronary artery disease. So it really an opportunity to be in a place where the technology was coming along, where we have discovered all these variants, clinical medicine of course has come a long way since the 1960s as well. So the idea was to really put these two bodies of work together, and see what we could come up with. Naveen Pereira: Yeah. This is very exciting. Amit, I completely agree with you. In our clinical practice we see patients with strong familial history of coronary artery disease, so certainly inheritance has been suspected for some time, and in fact genome-wide association studies have been done to identify loci for coronary artery disease. As you know, the effect size of these individual variants have been small. And so groups have got together to form genetic risk scores, where they take kind of an aggregate of the effect of these individual variants, and we think this is more helpful. And this is what you did for your paper, so can you describe to us a little bit about how you derived the genetic risk score that you applied in this great paper? Amit Khera: Sure. The first aspect of our paper involved proving basically that we could quantify someone's genetic risk for having a heart attack. So in order to do that, as you said, we took advantage of a number of previously published genome-wide association studies. There are about 50 genetic variants all across our genome and different chromosomes that we know are strongly linked to coronary artery disease from a statistical standpoint, but actually might only have a very modest impact on coronary disease. So let's say any individual could have a maximum of 100 risk variants. Now, some people might have inherited just by chance 80 variants, and other people might have inherited only 20. So we basically genotyped, meaning measured all 50 genetic variants in a large number of people, and then we said, "Those who are in the top quintile," meaning the top 20% of the genetic risk score, we're going to say "those people are at high genetic risk." And by contrast, if you're in the lowest quintile, we said, "Okay, those people are at low genetic risk." Naveen Pereira: Right. Amit Khera: Then the question became okay, well does that categorization actually predict your risk of having a heart attack? So in order to do that, we analyzed over 50,000 individuals from three different prospective cohort studies, and what we found actually was that if you compare the high genetic risk to the low genetic risk people, their risk for having a coronary event over prospective follow up was increased by about 91%, meaning almost two fold. Naveen Pereira: Wow. Oh, that's amazing. So using the genetic risk score, you could almost predict a doubling of the risk for coronary events. That's fantastic. Can you describe these populations briefly, Amit? Who are these people that you applied the genetic risk score to? Amit Khera: Sure. So we took advantage of three prospective cohort studies. The first was a Atherosclerosis Risk in Communities study, and that was a community based population of about 8,000 people. The second was the Women’s Genome Health Study, over 20,000 women who were originally recruited as part of a randomized control trial, and the third was the Malmö Diet and Cancer Study, which again had more than 20,000 individuals. The really nice thing about these studies was that they were asked questions in a similar way, and they were followed ... in each case, participants were followed for about 20 years. So we really had a long time to observe what happened to these folks over time. Naveen Pereira: So these are really longitudinal cohorts, not specifically disease oriented cohorts, but just community based, Amit? Amit Khera: That's exactly right, and in fact none of the individuals had coronary disease at baseline. They were all disease free- Naveen Pereira: I see. Amit Khera: ... and then we followed them over 20 years to see who developed the coronary artery disease and who did not. Naveen Pereira: So this is really applicable to the general population. Amit Khera: I do believe that these risk estimates would for sure hold true. Naveen Pereira: Okay, wonderful. So Amit, you know you have the genetic risk score for coronary artery disease, and you have some great longitudinally followed population based cohorts, and you were studying a specific phenotype, so can you describe to us the phenotype? Amit Khera: Well, the primary outcome phenotype was incident coronary events, and those were all adjudicated by different committees, but it basically involved individuals who had either a new heart attack or myocardial infarction, they had to have one of their vessels either stented or bypassed via revascularization, or in fact it was determined that they died from coronary artery disease. So that was the outcome which we were trying to predict. Naveen Pereira: Amit, let's get straight into it. What did you find? Amit Khera: So as a preventive cardiologist, I often see patients in my clinic who come to me and they say, "You know, almost everyone in my family has had a heart attack." Oftentimes at a very young age, and in some cases that can lead to almost a sense of determinism, where they feel like maybe they are unable to control their fate. So our primary question was a really a pretty simple one, which is to what extent can a healthy lifestyle offset someone's genetic risk of coronary disease. So as I mentioned, we had a way of quantifying someone's genetic risk, and then we next said, "Okay, we want to quantify someone's lifestyle risk." So for that we kept it pretty simple. We had four criteria of what makes up a healthy lifestyle. First, no current smoking. Second, avoiding obesity. Three, regular exercise, and fourth, adhering to a healthy diet. And we said, "Okay, if you have at least three out of those four," we gave you a pass and said "you had a favorable lifestyle." Now if you had only zero to one out of those four, you had an unfavorable lifestyle. One of the interesting things was that actually the genetic risk and the lifestyle risk actually were totally independent. There was no association for example between those who had high genetic risk and what their lifestyle was. So it really reinforced longstanding views that genetics and lifestyle are really independent axes of someone's individual level of risk. Now- Naveen Pereira: So both, Amit, both could contribute to your individual risk for coronary artery disease? Amit Khera: Exactly. As I mentioned, the high genetic risk versus low genetic risk, there was about a two fold difference in risk, and we saw an almost identical pattern versus a favorable lifestyle versus an unfavorable lifestyle. There was about a two fold risk [inaudible 00:17:08]. Naveen Pereira: Interesting. Amit Khera: Then that got us to the next question, which is to say if we analyze only those at high genetic risk so everyone had a similarly increased degree of genetic risk, to what extent could that risk be offset by a favorable lifestyle? This really gets back to the questions and the conversations we have with our patients who have a family history all the time. What we found there I think was a nice message, was that if you are at high genetic risk, you could actually decrease your risk by about 50% if you adhered to a favorable lifestyle, as compared to those with an unfavorable lifestyle. So for example, when we looked at it in absolute terms, in terms of a 10 year risk of having a coronary event, in one of the cohorts, those with a high genetic risk but an unfavorable lifestyle had about an 11% chance of having a coronary event, versus if you had the same high genetic risk but a favorable lifestyle, your risk was only about 5%. And we saw that, a very consistent pattern across all the cohorts and all the categories of genetic risk, that those who had a favorable lifestyle ... the risk was decreased by about 50% in those with a favorable lifestyle. Naveen Pereira: So that's fascinating, Amit. When physicians see a patient who have a really strong history of coronary artery disease within the family, and come up to you and say, "Doc, am I destined to have a heart attack?" You know, now with the availability of genotyping, with direct to consumer testing, people can find out their genetic risk. So they may not necessarily be doomed. Their fate is not predetermined. What you're suggesting is that fate can be modifiable. Amit Khera: Right. I think certainly for coronary disease your DNA is not your destiny, at least for these common variants. I think we provide evidence that really lifestyle factors powerfully modify your risk, really regardless of your genetic risk profile. Naveen Pereira: So Amit, can we make any recommendations based on the results of your paper? Amit Khera: Well, I think ... The American Heart Association has really endorsed these four lifestyle criteria as a way of improving the population's health in the population as a whole, and I think actually that our results actually support that. Which is to say that this really supports the fact that these healthy lifestyle parameters are critically important for everyone, and I think that's a good starting point. Genomic medicine is actually in its early days, but really what we hope to do is first to identify individuals, a subset of the population, who are at increased risk for a disease like heart disease, and I think we've shown that we can actually do that reasonably well. Like 20% of the population has a double risk. And the second part is actually to disclose this risk to both the patients and their providers in a way that's meaningful. And third, is actually demonstrate that we can actually implement the therapy to mitigate this increased risk. So I think we, in this paper, we provided evidence that a healthy lifestyle can mitigate that risk. Papers from our group, both published and some in press, have actually demonstrated that taking a statin can also powerfully modify this increased risk. And you might imagine that there may be other interventions that ... especially if an intervention has increased risk, you really may want to target it to those people who actually ... if a medicine has increased side effects, you may want to target it to those at the highest risk. I think that, you know, this polygenic risk score does provide at least one way of stratifying people into those high risk groups. Naveen Pereira: Yeah. Amit, really impressive results, 50% relative risk reduction in a high genetic risk population. You make a compelling argument. Obviously, however, this is not a prospective randomized clinical trial. It's really hard to do these. You had the advantage of well designed cohorts to study this in a cross sectional way. We don't know how these behaviors change. So these are some of the limitations, but the results are quite compelling, and contribute to the literature. Any other comments, Amit? Anything else that we should take home here? Amit Khera: No, I think as you said, there are some limitations. I think our really goal was to lay the foundation for future efforts where we really think about what the optimal way is for genetic information to be integrated into routine clinical practice to help prevent disease, and that's really what our group is planning on focusing on for the future years. Naveen Pereira: We look forward to hearing more exciting results from your laboratory, Amit. It's been a pleasure. We should end I guess with a quote from William Shakespeare, "It's not in the stars to hold our destiny but in ourselves." Correct? Amit Khera: Thank you very much. Sounds great. Naveen Pereira: Thanks, Amit. Jane Ferguson: So as we just heard from Naveen and Amit, the combination of genetic risk and modifiable lifestyle parameters are crucial in determining CAD risk. A recent AHA statement from the FGTB Council focused on this topic. The statement, entitled Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment, focused on how dietary and genetic contributors to disease have been studied in the past, and how emerging omics technologies can be used to rapidly advance these fields. Genomics, transcriptomics, metabolomics, proteomics, lipidomics, epigenetic profiling, and metagenomic characterization of the microbiome can all be used alone or in combination to better understand mechanisms underlying gene-environment contributions to disease. While the ultimate goal would be the development of improved therapeutic options, including personalized and precision approaches, a considerable amount of research remains to be done before this goal can be clinically implemented. You can read this statement in the June 2016 issue of Circulation: Cardiovascular Genetics. Naveen Pereira: So, Jane, this has been an exciting first podcast. I really look forward to doing more with you. Jane Ferguson: Yeah. I think this is great, so thank you everyone for listening, and happy heart month. We will look forward to bringing you a podcast again next month. Naveen Pereira: Thank you.
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Dr. Gene Robinson is the Swanlund Chair of Entomology, Director of the Institute for Genomic Biology, and Director of the Bee Research Facility at the University of Illinois at Urbana-Champaign. He received his PhD in Entomology from Cornell University and joined the faculty of the University in 1989. Gene has received many awards and honors over the course of his career, including the Burroughs Wellcome Innovation Award in Functional Genomics, the Founders Memorial Award from the Entomological Society of America, a Fulbright Senior Research Fellowship, a Guggenheim Fellowship, and an NIH Pioneer Award. He is also a Fellow of the Animal Behavior Society, a Fellow of the Entomological Society of America, a Fellow of the American Academy of Arts & Sciences, and member of the US National Academy of Sciences. Gene is here with us today to tell us about his journey through life and science.
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Mon, 26 Mar 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/6749/ https://edoc.ub.uni-muenchen.de/6749/1/Roidl_Andreas.pdf Roidl, Andreas ddc:500, ddc:570, Fakultät für Biologie 0
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