#323 - CRISPR and the future of gene editing: scientific advances, genetic therapies, disease treatment potential, and ethical considerations | Feng Zhang, Ph.D.

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Eric Ravussin is a world-renowned expert on obesity, metabolism, and aging whose pioneering research has shaped much of what we understand today about energy balance and caloric restriction. In this episode, Eric shares insights from his cutting-edge work on energy expenditure—a critical factor in understanding how our bodies regulate weight and appetite. He discusses methods for measuring energy output, energy balance, food intake, and appetite regulation, and explores key studies on macronutrient manipulation. Eric then delves into the CALERIE study on caloric restriction, highlighting insights related to biomarkers of both primary and secondary aging. The conversation also covers the potential of GLP-1 agonists to replicate these effects and looks ahead to how AI and technology could transform metabolic research in the coming years. We discuss: Eric’s background and current work metabolism and measuring energy expenditure [3:00]; The science behind metabolic chambers for measuring energy expenditure, and the complexities of indirect and direct calorimetry [8:00]; The body's regulatory systems for maintaining energy balance and the primary influence of energy intake on body weight [18:30]; The epidemic of obesity and a discussion of resting metabolic rate [24:45]; The impact of exercise, appetite, gut hormones, and eating patterns on weight regulation [28:45]; Experiments looking at how macronutrient composition affects energy expenditure [38:45]; The challenges of studying diet in real-life settings, the potential of personalized nutrition, and how public health policy could play a role in guiding nutritional habits [51:00]; The importance of protein in the diet, the limitations of dietary data collection, and how AI could potentially transform nutrition science [1:08:15]; How Eric’s interest in caloric restriction (CR) began with Biosphere 2, metabolic efficiency's role in aging, and goals of the CALERIE study [1:15:15]; The CALERIE study: exploring the real-world impact of caloric restriction [1:28:00]; Notable findings from the CALERIE study after two years: sustained weight loss, participant retention, and more [1:40:00]; The effect of caloric restriction on the hallmarks of aging [1:47:00]; The challenge of applying CR to the general population, the potential of drugs and exercise to mimic the effects of CR [1:55:45]; Upcoming study comparing caloric restriction to time-restricting eating, and Peter’s takeaways from the discussion [2:02:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Feng Zhang, a professor of neuroscience at MIT and a pioneering figure in gene editing, joins Peter to discuss his groundbreaking work in CRISPR technology, as well as his early contributions to optogenetics. In this episode, they explore the origins of CRISPR and the revolutionary advancements that have transformed the field of gene editing. Feng delves into the practical applications of CRISPR for treating genetic diseases, the importance of delivery methods, and the current successes and challenges in targeting cells specific tissues such as those in the liver and eye. He also covers the ethical implications of gene editing, including the debate around germline modification, as well as reflections on Feng’s personal journey, the impact of mentorship, and the future potential of genetic medicine. We discuss: Feng’s background, experience in developing optogenetics, and his shift toward improving gene-editing technologies [2:45]; The discovery of CRISPR in bacterial DNA and the realization that these sequences could be harnessed for gene editing [10:45]; How the CRISPR system fights off viral infections and the role of the Cas9 enzyme and PAM sequence [21:00]; The limitations of earlier gene-editing technologies prior to CRISPR [28:15]; How CRISPR revolutionized the field of gene editing, potential applications, and ongoing challenges [36:45]; CRISPR’s potential in treating genetic diseases and the challenges of effective delivery [48:00]; How CRISPR is used to treat sickle cell anemia [53:15]; Gene editing with base editing, the role of AI in protein engineering, and challenges of delivery to the right cells [1:00:15]; How CRISPR is advancing scientific research by fast-tracking the development of transgenic mice [1:06:45]; Advantages of Cas13’s ability to direct CRISPR to cleave RNA and the advances and remaining challenges of delivery [1:11:00]; CRISPR-Cas9: therapeutic applications in the liver and the eye [1:19:45]; The ethical implications of gene editing, the debate around germline modification, regulation, and more [1:30:45]; Genetic engineering to enhance human traits: challenges, trade-offs, and ethical concerns [1:40:45]; Feng’s early life, the influence of the American education system, and the critical role teachers played in shaping his desire to explore gene-editing technology [1:46:00]; Feng’s optimism about the trajectory of science [1:58:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Belinda Beck, founder of The Bone Clinic and a leading authority on exercise physiology and bone health, delves into the science of osteoporosis, bone density, and the lifelong importance of maintaining skeletal health. In this episode, she explains how the foundation for strong bones is established during childhood, offering valuable advice for parents on optimizing bone health for their kids. She also explores how bone remodeling occurs throughout life, driven by activity, nutrition, and hormones. Belinda highlights the power of resistance training in improving bone strength, even for those at risk of bone loss, and emphasizes the role of essential vitamins and minerals in maintaining bone health. She shares practical strategies, backed by research, for preventing fractures and combating osteoporosis. We discuss: Belinda’s journey into bone health research and training [2:45]; The physiology of bone and how bones adapt to mechanical loading [8:15]; Bone development from birth to adulthood, why early life is a crucial period, the functions of osteoblasts and osteoclasts, and gender differences in BMD [14:00]; How parents can optimize their children’s bone health through diet (calcium and vitamin D), sunlight exposure, and physical activity [27:30]; The best sports and activities for promoting bone health, weight training for kids, and advice for parents [36:30]; The impact of corticosteroid use on bone health in children and strategies to minimize negative effects [48:30]; Advice for people in middle age to preserve bone density: physical activity and bone-loading exercises [52:00]; Bone loss during the menopause transition for women: hormone replacement therapy and other strategies to mitigate BMD losses [59:30]; Interpreting the bone mineral density results from a DEXA scan: T-score, Z-score, and more [1:03:00]; The LIFTMOR study: testing the effects of heavy weightlifting on bone health in postmenopausal women with low bone density [1:10:15]; Profound benefits of weight training outside of BMD improvements: exploring the broader impacts on patients in the LIFTMOR study [1:19:30]; Guidance for people wanting to use exercise designed to improve their bone health [1:29:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Anna Lembke is the Chief of the Stanford Addiction Medicine Dual Diagnosis Clinic and author of Dopamine Nation: Finding Balance in the Age of Indulgence. In this episode, Anna dives deep into the biochemistry and neurobiology of addiction, exploring the critical role of dopamine and the prefrontal cortex. She shares her framework for diagnosing and treating addiction, providing real-world examples involving alcohol, gambling, cannabis, social media, and more. Anna outlines the risk factors for addiction, including inherited and nurture-based risks, explores the rise of addictions in younger generations, and discusses effective ways to address these issues with children. Additionally, she touches on healthy coping strategies, the evolution of the “marshmallow experiment,” and provides insights into GLP-1 agonists as a possible tool for addiction treatment. Finally, she reflects on the value of 12-step programs and how she navigates the emotional challenges of her work. We discuss: The role of dopamine and the prefrontal cortex in addiction [3:00]; The clinical definition of addiction and the behavioral criteria for diagnosing it [13:00]; Assessing alcohol use: patterns, risks, and addiction diagnosis [17:15]; Applying the addiction diagnosis framework using gambling as an example [21:45]; Exploring addiction variability: how nature, nurture, and access shape individual vulnerability and drug of choice [25:15]; How abstinence from addictive behaviors can help reset the brain’s reward system and improve mental health [41:15]; Safely abstaining from addiction substances, drugs needing medical supervision, and other key considerations [51:30]; Transitioning from abstinence to long-term recovery: tools and considerations [59:00]; Exploring behavioral addictions like sex addiction, and the gender differences in addiction patterns [1:08:30]; Factors contributing to the increasing levels of addiction across the world [1:13:45]; How online pornography can affect young boys' developing brains and lead to addictive behaviors, and strategies for parents to address this issue [1:23:30]; The link between social media use and declines in mental health, potential solutions, and protective measures [1:34:45]; How exercise affects brain chemistry, the role of dopamine and endorphins, and how exercise can become addictive [1:44:00]; Cold-water immersion for mood regulation, and other healthy coping strategies [1:47:15]; The “marshmallow experiment”: how broken promises affect behavior and trustworthy environments help children develop self-control [1:54:00]; Can GLP-1 agonists be useful in treating addiction? [1:58:30]; The benefits of 12-step programs [2:06:00]; Why understanding a patient’s story is essential for meaningful psychiatric care [2:11:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this “Ask Me Anything” (AMA) episode, Peter dives back into the increasingly popular topic of GLP-1 agonists, such as Ozempic and Mounjaro, which have garnered widespread attention for their ability to promote weight loss. Peter covers the latest findings in this rapidly evolving landscape, including new insights into their long-term efficacy, side effects, and what happens when the drug is discontinued. Peter also explores their impact on body composition and how resistance training interacts with these treatments. Additionally, he compares different GLP-1 receptor agonists and discusses promising new drugs in the pipeline. Finally, Peter addresses questions about the role of compounding pharmacies in the GLP-1 agonist market, compares oral vs. injectable options, and provides key considerations for anyone deciding whether to use a GLP-1 agonist for weight loss. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #64 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: The rapidly evolving landscape of GLP-1 agonists [2:15]; The mechanism of GLP-1 agonists, their origin as diabetes treatments, and how they evolved into weight-loss drugs [6:45]; Overview of new data and open questions related to the benefits and risks of GLP-1 agonists [10:30]; New insights into the long-term safety of GLP-1 agonists, side effects, and more [16:45]; The long-term efficacy of GLP-1 agonists, financial barriers, and more [19:45]; The mechanisms behind GLP-1 agonists' ability to promote weight loss [22:00]; New data on body weight changes after discontinuing the drug [26:00]; Effects of GLP-1 agonists on lean mass and body composition, and the role of protein and resistance training in preserving muscle [31:30]; Semaglutide vs. tirzepatide: comparing benefits and side effects [36:30]; How compounding pharmacies affect availability of GLP-1 drugs and the types of formulations that are available [39:15]; How do oral formulations of GLP-1 drugs compare to injectable formulations? [44:15]; How do sublingual (under tongue) formulations of GLP-1 drugs compare to injectable formulations? [46:15]; Guidance for using compounding pharmacies to purchase GLP-1 agonists [47:15]; Data on retatrutide—a promising new triple receptor agonist in the pipeline [50:15]; Can GLP-1 agonists be beneficial for sleep apnea and immune function? [57:00]; Potential neuroprotective benefits of GLP-1 agonists: impact on dementia risk [1:00:45]; Exploring why GLP-1 agonists may reduce the risk of cancer, kidney disease, and cardiovascular disease [1:04:00]; How GLP-1 agonists might boost fertility in women [1:10:15]; Early indications that GLP-1 agonists may help treat substance abuse disorders [1:12:00]; Potential health risks of GLP-1 agonists: addressing thyroid cancer concerns and the unknowns due to lack of data [1:14:00]; Examining the potential link between GLP-1 agonists and increased depression or suicidal ideation [1:16:00]; Major remaining questions: the effects of cyclic use, rebound appetite, impact on adolescents' development, and more [1:19:30]; Key considerations when deciding whether to use a GLP-1 agonist for weight loss [1:23:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this quarterly podcast summary (QPS) episode, Peter summarizes his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as liver health with Julia Wattacheril, heart rate variability with Joel Jamieson, artificial intelligence with Zak Kohane, klotho for brain health with Dena Dubal, and lactate and lactate metabolism with George Brooks. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the episode #319 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: Overview of topics, and the positive feedback on the quarterly podcast summary format [2:00]; Julia Wattacheril episode: liver health and disease [4:00]; Noninvasive methods to diagnose liver conditions, and how to manage and improve liver health [16:00]; Joel Jamieson episode: heart rate variability (HRV) for training and health [27:15]; Practical tools for measuring HRV and how it informs training and recovery decisions [37:00]; Zak Kohane episode: artificial intelligence and medicine [47:15]; The current role of AI in medicine and how it could revolutionize medicine in the future [53:45]; The limitations and concerns pertaining to AI [1:00:15]; Dena Dubal episode: the potential benefits of klotho for brain health [1:05:00]; Animal studies on klotho and brain health [1:11:00]; Genetics-based variations in klotho levels in humans and their impact on cognition, disease risk, and longevity [1:14:15]; Testing klotho levels, the significance of the KL-VS variant, the role of exercise in increasing klotho, and more [1:17:30]; The potential of klotho as a treatment for cognitive decline and Alzheimer's disease [1:23:15]; George Brooks episode: a new paradigm to think about lactate and lactate metabolism [1:27:45]; The potential for lactate infusions to aid in brain recovery following a head injury [1:34:00]; The relationship between lactate and cancer, and the impact of exercise on lactate levels and cancer risk [1:36:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Tadej Pogačar is a three-time Tour de France champion and one of the most dominant cyclists of his generation. In this episode, he shares insights into his 2020 Tour de France victory, his historic 2024 season winning both the Giro d’Italia and Tour de France, and the struggles he faced in 2022 and 2023. He also dives into his training regimen, nutrition, and the key metrics he tracks, like power, VAM, and heart rate variability. Tadej offers a glimpse into his goals for the future and what it takes to stay at the top of the sport. We discuss: 2020 Tour de France win [4:30]; Learning from previous mistakes [8:45]; Training: simulating steep climbs and other challenging race conditions [10:30]; Tadej’s historic 2024 season and what contributed to his success [12:30]; Nutrition for optimal performance: offseason diet and carbohydrate intake during intense training sessions [15:30]; Training metrics: heart rate, power output, VAM, and HRV, and his approach to zone 2 training [18:15]; Epic climbs in the Tour de France, mindset after challenging stages, and rebuilding confidence after the 2023 Tour [25:45]; Racing dynamics, media criticism, and Tadej’s reflections on racing records [32:15]; Training in the off-season [39:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Marty Makary, a Johns Hopkins surgeon and New York Times bestselling author, returns to The Drive to discuss his latest book, Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. In this episode, Marty explores how a new generation of doctors is challenging long-held medical practices by asking critical new questions. He discusses the major problems of groupthink and cognitive dissonance in the medical community and delves into several of the "blind spots" raised in the book, including treatments for appendicitis, the peanut allergy epidemic, misunderstandings about HRT and breast cancer, antibiotic use, and the evolution of childbirth. He explains the urgent need for reform in medical education and the major barriers standing in the way of innovative medical research. Throughout the conversation, Marty offers insightful reflections on where medicine has succeeded and where there’s still room to challenge historic practices and embrace new approaches. We discuss: The issue of groupthink and cognitive dissonance in science and medicine [2:30]; How a non-operative treatment for appendicitis sheds light on cognitive dissonance [7:00]; How cognitive dissonance and effort justification shape beliefs and actions [13:15]; How misguided peanut allergy recommendations created an epidemic [17:45]; The enduring impact of misinformation and fear-based messaging around hormone replacement therapy allegedly causing breast cancer [25:15]; The dangers of extreme skepticism and blind faith in science, and the importance of understanding uncertainty and probability [28:00]; The overuse of antibiotics and the rise of antibiotic resistant infections and poor gut health [33:45]; The potential correlations between early antibiotic use and chronic diseases [40:45]; The historical and evolving trends in childbirth and C-section rates [50:15]; Rethinking ovarian cancer: recent data challenging decades of medical practice and leading to new preventive measures [1:05:30]; Navigating uncertainty as a physician [1:19:30]; The urgent need for reform in medical education [1:21:45]; The major barriers to innovative medical research [1:27:30]; The dogmatic culture of academic medicine: why humility and challenging established norms are key for progress [1:38:15]; The major successes and ongoing challenges of modern medicine [1:51:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of hair loss, exploring its relationship with aging and its impact on quality of life. The conversation focuses on androgenic alopecia, the most common form of hair loss in both men and women, and covers the differences in patterns and causes between the sexes. Peter delves into the right timing for treatment, breaking down various options such as minoxidil and finasteride, low-level laser therapy, platelet-rich plasma injections, and more. Additionally, Peter outlines the pros and cons of the two primary hair transplantation methods and concludes with practical advice on selecting the right specialist or treatment team for those facing hair loss. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #63 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: The impact of hair loss on emotional health [2:15]; The prevalence, patterns, and causes of hair loss in men and women [5:15]; The genetic and hormonal causes of hair loss, and the role of dihydrotestosterone (DHT) in androgenic alopecia [8:45]; The visual differences in hair loss patterns between men and women, and the importance of consulting a specialist to rule out non-genetic causes of hair loss [13:30]; How genetic predisposition influences the risk of androgenic alopecia, and how early detection through diagnostic tools and blood tests can help manage risk more effectively [16:45]; Ideal timing for starting treatment: why early treatment is crucial for effectively managing hair loss [19:30]; The various FDA-approved treatments for androgenic alopecia, their mechanisms, and additional off-label treatments commonly used to manage hair loss [24:30]; Topical minoxidil—the most commonly recommended starting treatment for hair loss [30:15]; Oral vs. topical minoxidil: efficacy, ease of use, and potential side effects that must be considered [33:45]; Finasteride for treating hair loss: efficacy, potential side effects on libido, and the need for careful PSA monitoring in men to avoid missing early signs of prostate cancer [37:15]; Other effective hair loss treatments for women: boosting hair density with spironolactone gel and ketoconazole shampoo as part of a comprehensive strategy [41:30]; Low-level laser therapy: effectiveness, costs, practicality, and a comparison of in-office treatments with at-home devices [49:00]; Platelet-rich plasma (PRP) as a treatment for hair loss: potential effectiveness, varying protocols, and significant costs [53:45]; Hair transplant for advanced hair loss: criteria and considerations [58:00]; Types of hair transplants: follicular unit transplantation (FUT) vs. follicular unit extraction (FUE) [1:02:00]; The financial cost of hair transplant surgery, and what to consider when seeking affordable options [1:06:15]; The potential risks and downsides of the various hair transplant procedures [1:09:30]; Post-procedure care for hair transplants and whether the procedure must be repeated periodically [1:16:30]; Combining different hair loss treatments: benefits, risks, and considerations [1:18:30]; Emerging hair loss treatments with limited data [1:21:00]; Key considerations for selecting the right treatment plan for hair loss [1:22:00]; A summary of the different considerations for men and women facing hair loss [1:24:30]; Practical advice on selecting the right specialist or treatment team [1:26:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this episode, former World Series of Poker champion and author Annie Duke explains how poker is a pertinent model system for decision-making in the real world, a system which blends imperfect information with some unknown percentage of both luck and skill. Annie breaks down the decision-making matrix, revealing how we often focus too narrowly on just one of the four quadrants, missing out on valuable learning opportunities in the remaining 75% of situations. She delves into how our tendency to evaluate only negative outcomes leads to a culture of risk aversion. This mindset, she argues, stifles the kind of bold decision-making necessary for progress and innovation across various fields, from poker and sports to business and medicine. Annie also introduces a robust framework for learning and the levels of thought required to excel in any domain. Finally, she discusses a strategy called “backcasting”, a concept that resonated deeply with Peter in terms of how he thinks about extending healthspan. We discuss: Annie’s background, favorite sports teams, and Peter’s affinity for Bill Belichick [1:30]; Chess vs. poker: Which is a better metaphor for decision-making in life (and medicine)? [6:45]; Thinking probabilistically: Why we aren’t wired that way, and how you can improve it for better decision-making [12:30]; Variable reinforcement: The psychological draw of poker that keeps people playing [19:15]; The role of luck and skill in poker (and other sports), and the difference between looking at the short run vs. long run [32:15]; A brief explanation of Texas hold ‘em [41:00]; The added complexity of reading the behavior of others players in poker [47:30]; Why Annie likes to “quit fast,” and why poker is still popular despite the power of loss aversion [52:45]; Limit vs. no-limit poker, and how the game has changed with growing popularity [55:15]; The advent of analytics to poker, and why Annie would get crushed against today’s professionals [1:04:45]; The decision matrix, and the “resulting” heuristic: The simplifier we use to judge the quality of decisions —The Pete Carroll Superbowl play call example [1:10:30]; The personal and societal consequences of avoiding bad outcomes [1:21:45]; Poker as a model system for life [1:31:30]; How many leaders are making (and encouraging) status-quo decisions, and how Bill Belichick’s decision-making changed after winning two Super Bowls [1:35:15]; What did we learn about decision-making from the Y2K nothingburger? And how about the D-Day invasion? [1:39:30]; The first step to becoming a good decision maker [1:43:00]; The difference between elite poker players and the ones who make much slower progress [1:49:45]; Framework for learning a skill, the four levels of thought, and why we hate digging into our victories to see what happened [1:52:15]; The capacity for self-deception, and when it is MOST important to apply four-level thinking [2:00:30]; Soft landings: The challenge of high-level thinking where there is subtle feedback and wider skill gaps [2:11:00]; The benefits of “backcasting” (and doing pre-mortems) [2:13:30]; Parting advice from Annie for those feeling overwhelmed (and two book recommendations) [2:21:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube