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This week on The Genetics Podcast, Patrick goes solo to look at what recent AI breakthroughs in mathematics could mean for biology. He discusses the OpenAI results on the Navier-Stokes equation and hundreds of open math problems, what makes math and code so easy for AI to improve on, how self-driving labs and surrogate endpoints could speed up drug development, and where the biggest gaps and opportunities remain. Show Notes 0:00 Intro to The Genetics Podcast 00:58 What the OpenAI math breakthroughs could mean for biology 02:57 AI’s recent frontier math results and how mathematicians reacted 09:12 Lean as a proof checker and why it matters for math 10:44 Four conditions behind AI’s math progress and how biology compares 16:22 Why verification speed decides where AI can accelerate biology 19:35 How lab automation shortens feedback loops for variants and antibodies 23:13 How validated biomarkers let early trials predict clinical outcomes 26:11 Why validated surrogate endpoints could speed up drug development 31:58 How startups and big pharma are building self-driving labs 33:40 Virtual cell models built from perturbation data 34:50 Genetics-driven drug discovery and the Phase II success rate question 37:42 Verification speed and surrogate endpoints as biology’s biggest gaps 40:38 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Sek Kathiresan, CEO of Verve Therapeutics and SVP, Head of Obesity Research and Early Development at Eli Lilly. They discuss how protective genetic variants led to the development of a one-time gene editing therapy for heart disease in the face of early doubt, the phase one results for Verve-102, what recent trial failures mean for genetic target validation, and the unmet needs in obesity treatment. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Sek  01:40 Sek’s family history of heart disease and how it motivated him to pursue cardio therapeutics 03:29 Sek’s background and research on the genetics of coronary artery disease and protective mutations 08:03 Reactions to the Verve launch and the biological, technological, regulatory, and commercial risks 11:00 Verve-102 phase one results and the case for lifelong LDL lowering 16:14 Why cumulative exposure means lowering LDL earlier and for longer 17:53 Recent trial failures in genetically validated targets and what the Lp(a) trial leaves unanswered 20:33 Polygenic risk scores and who benefits most from LDL lowering 23:36 Sek’s new role at Lilly and the remaining unmet needs in obesity treatment 29:06 Whether one-time gene therapy could work for obesity and how GLP-1 drugs drive weight loss 30:38 Food intake, energy expenditure, and the search for new obesity mechanisms 32:15 Why Lilly is investing so heavily in genetic medicine 34:35 Closing remarks Find out more ANGPTL3 study in NEJM (https://pmc.ncbi.nlm.nih.gov/articles/PMC3008575/) Verve-102 study (https://www.nejm.org/doi/10.1056/NEJMoa2601283)

This week on The Genetics Podcast, Patrick is joined by Dr. Luke Pilling, Senior Lecturer in Genetic Epidemiology at the University of Exeter. They discuss hemochromatosis and the case for earlier diagnosis, and the genetic drivers of multimorbidity, pharmacogenetics, and drug response. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Luke  01:37 An overview of HFE hemochromatosis and why diagnosis is delayed  04:24 Iron levels and overload risk in heterozygous and compound heterozygous carriers 05:51 Aging-related effects seen in homozygotes  06:43 How hemochromatosis is currently diagnosed and detected in the UK 09:26 Future screening and case finding, including the Our Future Health cohort 11:28 Genetic and environmental factors that shape outcomes in C282Y homozygotes  13:28 The GEMINI project and the genetic drivers of multimorbidity 15:56 Drug targets from multimorbidity genetics, including repurposing and opposite effects 18:49 Using disease sequences in health records to look for earlier intervention points in multimorbidity 21:21 Data gaps limiting multimorbidity research, from primary care records to proteomics 23:17 Handling misdiagnosis and clinical code accuracy in health record research 24:55 International collaborations and the need for more diverse biobank data 26:08 Pharmacogenetics research and how genetic variants shape drug response 29:04 Limited clinical examples of pharmacogenetics and lessons from non-responders 33:08 Genetics of lifespan and healthy aging, and why geroscience pathways rarely appear in GWAS 36:06 Luke’s future research focuses  40:39 Closing remarks Find out more: - Hereditary hemochromatosis study - Multimorbidity study - Pharmacogenetics framework study

This week on The Genetics Podcast, Patrick is joined by Dr. James Zou, Associate Professor of Biomedical Data Science at Stanford University. They discuss the concept of virtual biotechs and how AI agents link single cell data to clinical trial success, Paper to Agent and turning papers into living virtual authors, clinical AI from EchoNet to SleepFM, and the role of academia alongside big AI labs. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to James  01:55 An overview of James’s virtual biotech and its AI scientist agents 04:11 How single cell evidence behind drug targets predicts clinical trial success 06:33 Behind the scenes of how autonomous the virtual biotech agents are 08:06 Missing proprietary trial data as the next gap for the virtual biotech 09:44 Scaling the number of collaborating AI agents as a new frontier for drug discovery 12:29 How teamwork and structure evolved among the agents  15:53 Behind the idea of Paper to Agent and virtual authors 19:01 What converting over 100 papers into agents revealed about reproducibility 23:14 The story behind EchoNet, an FDA-cleared AI tool for cardiac ultrasound 26:28 Predicting risk for over 100 future diseases from one night of sleep 27:40 Transferring SleepFM from sleep labs to consumer wearables 28:43 Combining multimodal health data to predict disease 30:10 Longitudinal blood proteomics as the biggest data gap for health AI 31:18 The role of academia as an open, neutral counterweight to big AI labs 32:51 How James’s path from Cambridge math and Harvard machine learning led to biology 34:41 Closing remarks Find out more Virtual biotech paper (https://www.science.org/doi/10.1126/science.aeg6779) Paper2Agent paper (https://www.nature.com/articles/s41586-026-11044-y)

This week on The Genetics Podcast, Patrick is joined by Dr. Jeffrey Barrett, Group Leader at the Ellis Institute Finland and the University of Helsinki. They discuss using AI and federated biobank data to stratify common chronic diseases, how LLMs reading clinical notes in Finland's health registries can reveal treatment response, how AI is changing the way scientists research and train, and what the UK's COVID genome sequencing effort means for biosecurity. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Jeff  02:08 Jeff's research focus for his new lab, including molecular subtyping of common chronic diseases with AI 06:18 Barriers to pooling biobank data across research environments for federated AI models 11:00 Why Jeff expects larger datasets to make complex models better at predicting disease 13:34 The three disease areas Jeff's lab will target first: cardiometabolic, inflammatory and neuropsychiatric 19:41 Using LLMs to read clinician notes in Finland's health registries for treatment response 24:50 How Jeff uses AI in his research and where humans still need to read and review 31:08 Using Claude to understand papers and the gaps in its literature searches 32:14 Jeff on AI solving open problems in mathematics and biology, and where researchers fit 35:48 Simultaneous discoveries and why lab data generation still needs experts 39:01 Jeff's COVID genome sequencing at Sanger and what it means for AI and biosecurity 43:16  Closing remarks

Summary This week on The Genetics Podcast, Patrick is joined by Jenny Hsieh, Co-Founder and President of the Danon Foundation. They discuss how Danon disease affects males and females, why it is so often misdiagnosed, the current therapy landscape and research priorities, and how families can make informed decisions about gene therapy trials. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Jenny  01:28 An overview of Danon disease 02:34 Sex differences in Danon disease and severe disease in females 05:15 Why Danon disease is misdiagnosed and how it may be spotted earlier 08:50 Therapy pipeline for Danon and the Foundation's global patient coordination 13:46 Origin story of the Danon Foundation 18:10 Research priorities and the burden of Danon disease beyond the heart 22:39 Raising genetic testing awareness among ophthalmologists and cardiologists for Danon disease 25:20 Recognizing broader Danon symptoms and launching the first Danon Awareness Day 29:37 Informed consent and trial literacy for families weighing gene therapy 33:14 Patient-friendly trial experiences 36:19 Ways to support Danon research 37:37 Closing remarks Find out more Danon Foundation

This week on The Genetics Podcast, Patrick is joined by Dr. Inigo Martincorena, Group Leader at the Wellcome Sanger Institute. They discuss the discovery of widespread cancer-driver mutations in normal tissue, the role of somatic mutations in autoimmune disease, new sequencing technologies transforming the field, and the therapeutic potential of targeting these mutations. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Inigo  01:46 How Inigo's eyelid skin study revealed widespread cancer-driver mutations 07:14 Findings from a follow-up study on esophageal tissue 10:02 How NanoSeq technology scaled somatic mutation research across tissues 12:34 The thyroid study linking somatic mutations to autoimmune disease 17:07 How escaped B cell clones evolve into polyclonal autoimmune disease 20:21 Immune gene mutations occurring in healthy aging lymphocytes 21:21 Why driver mutation clones in normal tissue rarely become cancer 24:16 Two therapeutic paradigms for targeting somatic mutations in disease 28:13 Examples of somatic rescue mutations in the colon, liver, and blood 29:20 Why clonal selection only occurs in dividing cell types 31:20 The field's remaining blind spots in mobile immune cells and rare samples 33:46 How new single-cell sequencing will link genotype to phenotype 36:03 What Inigo has learned from collaborating across Sanger's expertise 38:09 Closing remarks Find out more Eyelid study Esophagus study

This week on The Genetics Podcast, Patrick is joined by Dr. Marleah Dean Kruzel, Professor of Communication at the University of South Florida. They discuss her personal path from watching breast cancer move through her family to testing positive for a hereditary mutation herself, the ART framework she developed for managing uncertainty, and the complexities of communicating genetic risk within families. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Marleah 01:35 Marleah's family history of breast cancer across four generations 02:48 Marleah's childhood living through her mother's five-year cancer battle 04:26 Marleah's experience with genetic testing 07:19 How a positive test result reshaped Marleah’s PhD research focus 08:40 The central challenges of living with a positive test result  10:50 The ART framework for managing hereditary cancer uncertainty 15:06 Applying the ART framework to Patrick’s experience with uncertainty and the importance of having a support system  19:53 Common misconceptions in how families communicate genetic risk 23:54 The previvor identity and the chronic uncertainty it brings 25:40 How Marleah has learned to accept and embrace uncertainty 27:57 Balancing logic and emotion in hereditary cancer family planning 31:28 How Marleah grounds her research tools in patients' lived experience 33:21 How AI is eroding our capacity to sit with uncertainty 35:57 Redesigning healthcare for a lifespan of genetic risk information 38:10 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. David Hallett, Chief Scientific Officer at Recursion. They discuss the biggest shifts in drug discovery over Dave's three-decade career, where AI is genuinely transforming the field today versus where the hype outruns the reality, and how Recursion's perturbational maps have uncovered and validated a novel neurodegeneration target. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Dave 01:57 The biggest shifts in drug discovery over three decades 06:39 Where AI is delivering real wins across drug discovery today 12:19 How AI-assisted trial simulation reveals which eligibility criteria to relax 14:46 The three biggest reasons drug programs fail in the clinic  18:20 How Recursion's perturbational maps uncover new drug targets 24:58 A four-step framework for validating a novel drug target 28:44 How Recursion balances deep therapeutic focus with partnership breadth 30:52 Why AI can't shortcut clinical trials, and what proof of real impact looks like 34:57 The skills scientists need most in the AI era, and why trusting AI outputs starts with trusting the data 39:52 Closing remarks Find out more: Recursion (https://www.recursion.com/)

This week on The Genetics Podcast, Patrick is joined by Dr. Danny Miller, Assistant Professor of Pediatrics and of Laboratory Medicine and Pathology at the University of Washington and Attending Physician at Seattle Children's Hospital. They discuss the case for making long-read sequencing the first genetic test every patient receives, the reference dataset his lab is building from the 1000 Genomes Project to resolve structural variants, publicly available methylation signatures as biomarkers for diagnosis and treatment response, and his vision for genome-informed care from newborn screening through the NICU. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Danny 01:41 The case for long-read sequencing as first-line genetic testing 02:52 Current barriers to wider use of long-read sequencing  04:14 Building a long-read reference dataset from 1000 Genomes for variant filtering 06:47 How long-read sequencing can solve a missed diagnosis  08:12 The clinical case for complete telomere-to-telomere genomes 10:39 What it will take to shift the clinical genetics status quo 12:06 Making methylation signatures public to diagnose disease and track therapy 15:58 Danny's path from programming and finance into clinical genetics 18:19 Danny's lived experience with deafness and achondroplasia, and how it shapes his approach to genetic counseling 21:46 Danny's optimism about AI in genomics and worry about AI in education 27:15 The path to making genomes a routine part of the medical record 29:47 The vision of same-day newborn genomic data guiding NICU treatment decisions 34:31 Closing remarks Find out more: Miller Lab (https://millerlaboratory.com/)

This week on The Genetics Podcast, Patrick is joined by Dr. Brent Richards, CEO and Founder of 5 Prime Sciences and Professor of Human Genetics, Epidemiology, and Medicine at McGill University. They discuss how to triangulate different types of genetic evidence to validate a drug target, why herd psychology often drives which targets get funded, why strong genetic support didn't save the Zeus IL-6 trial, and how collider bias can distort genetically stratified clinical trials. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Brent 01:43 How company size shapes access to genetic drug discovery tools 04:10 Brent's framework for triangulating different types of genetic evidence 06:50 The herd psychology behind which drug targets get funded 10:01 Potential reasons the Zeus IL-6 trial failed despite strong genetic evidence 12:49 What a gold standard genetic evidence package actually looks like  17:13 Closing the data gap with diverse genomes and systematic pipelines 19:03 The diabetes patient story that drove Brent into drug development and balancing academia with industry 25:39 Why obesity went from a drug development graveyard to its biggest frontier 29:13 How collider bias can distort genetic risk trial results 38:20 Where to go deeper on advanced genetic drug discovery concepts 40:11 Closing remarks Find out more: 5PrimeSciences’ symposium on human genetics at ASHG2026 in October

This week on The Genetics Podcast, Patrick is joined by Dr. Andrew Jackson, Programme Leader at the MRC Human Genetics Unit at the University of Edinburgh. They discuss how his lab discovered that gain-of-function DNMT3A mutations cause both microcephalic dwarfism and an accelerated aging syndrome, and what that reveals about the shared biology of growth and aging. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Andrew 01:34 The origins of Andrew's work linking brain size and aging 02:54 The genetics of mammalian size range and epigenetic factors regulating growth 05:02 How DNMT3A mutations causing dwarfism led to discovering an accelerated aging syndrome 09:46 Cell number rather than cell size as the shared driver of growth and aging 13:07 Whether brain size within humans actually predicts cognitive ability 15:20 Why intellectual disability has far more known genes than dwarfism 19:26 Discovering ribonuclease H2's role in DNA repair, and its unexpected link to cancer  23:35 Why studying rare monogenic diseases reveals broader biology 26:59 Andrew's next research questions on aging, cancer, and mutation biology 28:42 Why humans, model organisms, and cell assays each have a role 31:00 Somatic mosaicism's growing role in aging and disease beyond cancer 36:11 Closing remarks Find out more: Mentioned studies from Andrew’s lab:  https://www.nature.com/articles/s41588-026-02633-8 https://www.nature.com/articles/s41588-018-0274-x

This week on The Genetics Podcast, Patrick is joined by Stevie Ringel, co-founder of Nome and founder of the Kizuna Foundation. They discuss Stevie's own ultra-rare disease diagnosis and shaped his path to founding Kizuna Foundation and Nome, how Nome's AI agents help scientists navigate the operational complexity of small-batch drug development, the technical and business model advantages underpinning Nome's accuracy, and what it will take to build a sustainable funding model for ultra-rare disease. Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Stevie 01:37 Stevie's inherited retinal disease (IRD) diagnosis and subsequent path into genomics 03:16 Why Stevie founded Kizuna Foundation and why ultra-rare drug development is so operationally complex 06:27 The origin story of Nome and using AI to automate the operational work  10:09 The inspiration for the name “Nome” and who the company is built to serve 12:44 The biggest blockers to program speed 15:07 How AI and scale can bring down the cost of gene therapy manufacturing 18:01 FDA signals and global regulatory competition  19:33 Priority review vouchers and why Nome stays out of molecule IP 20:33 Nome's AI and review process for patient reports and its expansion to health systems 25:04 Nome's agent architecture and the data behind its accuracy 28:17 Why delivery remains gene therapy's biggest bottleneck and approaches for solving it 31:34 The case for a new capital model in rare disease drug development  33:25 What’s next for Nome as they advance preclinical programs 34:25 Nome’s focus on process excellence across therapeutic modalities 36:34 Closing remarks Find out more: Nome

This week on The Genetics Podcast, Patrick is joined by Dr. Jagesh Shah, Chief Scientific Officer at Mirai Bio. They discuss why delivery is a central bottleneck holding back nucleic acid medicines, how Mirai's lipid nanoparticle (LNP) platform is built to reach tissues like adipocytes and T cells, and the machine learning feedback loop the company uses to engineer LNP formulations. Show Notes 0:00 Intro to The Genetics Podcast 01:00 Welcome to Jagesh 01:40 Why delivery is the main bottleneck for gene therapies 03:42 Easier vs harder tissues to target for delivery 06:40 Overview of Mirai's modular delivery platform  09:02 Comparing viral vectors and lipid nanoparticles (LNPs)  12:18 Different approaches for targeting adipocytes and T cells with LNPs 15:49 Mirai's machine learning (ML) feedback loop for optimizing LNP formulation 20:50 Why lipid chemistry is still hard for ML to learn and factors affecting LNP tropism 24:35 Jagesh's path from academia to Mirai 27:23 Mirai's platform business model and how it lowers risk 29:13 What industry partnerships with Mirai look like 31:41 Mirai's next frontier of delivery to muscle tissue and the brain  34:40 Cargo size and immunogenicity of LNPs vs AAV  36:00 Why the field needs to close the regulatory pace gap  37:19 Closing remarks Find out more: Mirai Bio

This week on The Genetics Podcast, Patrick is joined by Sharon Terry, President & CEO of Genetic Alliance. They discuss how Sharon established a layperson-led biobank, her long-term work on rare diseases and patient advocacy, and her program to bring genetic technology to patients in low- to middle-income countries. We’re re-running this episode for its enduring lessons on patient advocacy, rare disease parenting, communication, and citizen science.  Show Notes 0:00 Intro to The Genetics Podcast 00:59 Welcome to Sharon and a discussion of the personal experience with rare disease that started her journey 03:47 Reasons Sharon decided to establish the first layperson-led biobank 05:34 Challenges with setting up the biobank infrastructure 07:00 Balancing financial factors in a non-profit organization  09:30 Recent patterns and future insight into rare disease drug discovery framework and regulation 15:32 Barriers to widespread collaboration and cooperation in rare disease research, and why it should be approached from a public health perspective 18:12 Background and experiences from the iHope Genetic Health program in low- to middle-income countries 24:44 Sharon’s perspective on challenges with the Genetic Information Non-discrimination Act 28:49 Sharon’s lessons learned in her patient advocacy and policy work, and her hopes for future legislation 33:04 Sharon’s hopes for improved access to genetic testing and treatment for children in underserved communities 34:34 How Sharon learned about rare diseases and genetics as a “homeschooling mom without a degree” 37:54 Insights into how elements of spirituality can support advocacy work 40:18 Closing remarks