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 Notes0:00 Intro to The Genetics Podcast01:00 Welcome to Dave01:57 The biggest shifts in drug discovery over three decades06:39 Where AI is delivering real wins across drug discovery today12:19 How AI-assisted trial simulation reveals which eligibility criteria to relax14:46 The three biggest reasons drug programs fail in the clinic 18:20 How Recursion's perturbational maps uncover new drug targets24:58 A four-step framework for validating a novel drug target28:44 How Recursion balances deep therapeutic focus with partnership breadth30:52 Why AI can't shortcut clinical trials, and what proof of real impact looks like34:57 The skills scientists need most in the AI era, and why trusting AI outputs starts with trusting the data39:52 Closing remarksFind 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 Notes0:00 Intro to The Genetics Podcast01:00 Welcome to Danny01:41 The case for long-read sequencing as first-line genetic testing02:52 Current barriers to wider use of long-read sequencing 04:14 Building a long-read reference dataset from 1000 Genomes for variant filtering06:47 How long-read sequencing can solve a missed diagnosis 08:12 The clinical case for complete telomere-to-telomere genomes10:39 What it will take to shift the clinical genetics status quo12:06 Making methylation signatures public to diagnose disease and track therapy15:58 Danny's path from programming and finance into clinical genetics18:19 Danny's lived experience with deafness and achondroplasia, and how it shapes his approach to genetic counseling21:46 Danny's optimism about AI in genomics and worry about AI in education27:15 The path to making genomes a routine part of the medical record29:47 The vision of same-day newborn genomic data guiding NICU treatment decisions34:31 Closing remarksFind 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 Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Brent01:43 How company size shapes access to genetic drug discovery tools04:10 Brent's framework for triangulating different types of genetic evidence06:50 The herd psychology behind which drug targets get funded10:01 Potential reasons the Zeus IL-6 trial failed despite strong genetic evidence12:49 What a gold standard genetic evidence package actually looks like 17:13 Closing the data gap with diverse genomes and systematic pipelines19:03 The diabetes patient story that drove Brent into drug development and balancing academia with industry25:39 Why obesity went from a drug development graveyard to its biggest frontier29:13 How collider bias can distort genetic risk trial results38:20 Where to go deeper on advanced genetic drug discovery concepts40:11 Closing remarksFind 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 Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Andrew01:34 The origins of Andrew's work linking brain size and aging02:54 The genetics of mammalian size range and epigenetic factors regulating growth05:02 How DNMT3A mutations causing dwarfism led to discovering an accelerated aging syndrome09:46 Cell number rather than cell size as the shared driver of growth and aging13:07 Whether brain size within humans actually predicts cognitive ability15:20 Why intellectual disability has far more known genes than dwarfism19:26 Discovering ribonuclease H2's role in DNA repair, and its unexpected link to cancer 23:35 Why studying rare monogenic diseases reveals broader biology26:59 Andrew's next research questions on aging, cancer, and mutation biology28:42 Why humans, model organisms, and cell assays each have a role31:00 Somatic mosaicism's growing role in aging and disease beyond cancer36:11 Closing remarksFind out more:Mentioned studies from Andrew’s lab: https://www.nature.com/articles/s41588-026-02633-8https://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 Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Stevie01:37 Stevie's inherited retinal disease (IRD) diagnosis and subsequent path into genomics03:16 Why Stevie founded Kizuna Foundation and why ultra-rare drug development is so operationally complex06:27 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 serve12:44 The biggest blockers to program speed15:07 How AI and scale can bring down the cost of gene therapy manufacturing18:01 FDA signals and global regulatory competition 19:33 Priority review vouchers and why Nome stays out of molecule IP20:33 Nome's AI and review process for patient reports and its expansion to health systems25:04 Nome's agent architecture and the data behind its accuracy28:17 Why delivery remains gene therapy's biggest bottleneck and approaches for solving it31:34 The case for a new capital model in rare disease drug development 33:25 What’s next for Nome as they advance preclinical programs34:25 Nome’s focus on process excellence across therapeutic modalities36:34 Closing remarksFind 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 Notes0:00 Intro to The Genetics Podcast01:00 Welcome to Jagesh01:40 Why delivery is the main bottleneck for gene therapies03:42 Easier vs harder tissues to target for delivery06:40 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 LNPs15:49 Mirai's machine learning (ML) feedback loop for optimizing LNP formulation20:50 Why lipid chemistry is still hard for ML to learn and factors affecting LNP tropism24:35 Jagesh's path from academia to Mirai27:23 Mirai's platform business model and how it lowers risk29:13 What industry partnerships with Mirai look like31:41 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 remarksFind 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 Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Sharon and a discussion of the personal experience with rare disease that started her journey03:47 Reasons Sharon decided to establish the first layperson-led biobank05:34 Challenges with setting up the biobank infrastructure07:00 Balancing financial factors in a non-profit organization 09:30 Recent patterns and future insight into rare disease drug discovery framework and regulation15:32 Barriers to widespread collaboration and cooperation in rare disease research, and why it should be approached from a public health perspective18:12 Background and experiences from the iHope Genetic Health program in low- to middle-income countries24:44 Sharon’s perspective on challenges with the Genetic Information Non-discrimination Act28:49 Sharon’s lessons learned in her patient advocacy and policy work, and her hopes for future legislation33:04 Sharon’s hopes for improved access to genetic testing and treatment for children in underserved communities34:34 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 work40:18 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Carl Anderson, Senior Group Leader and Head of the Human Genetics Programme at the Wellcome Sanger Institute, where he leads the Genomics of Inflammation and Immunity Group. They discuss IBDVerse, the single-cell atlas Carl's team built to map genetic effects on gene regulation across gut cell types, how coding and non-coding variants converge on shared biological pathways in inflammatory bowel disease, and Carl's vision for longitudinal multi-omics cohorts built around the sickest and most underrepresented hospital patients.Show Notes0:00 Intro to The Genetics Podcast00:58 Welcome to Carl02:05 The origins of IBDVerse and mapping genetic effects on gene regulation across gut cell types in IBD05:43 How anti-TNFs and newer genetically-supported IBD drugs have reshaped treatment 08:04 Genetic versus environmental contributions to IBD09:53 Using single-cell data to uncover IBD disease subtypes13:22 Drug sequencing and immunogenicity in treatment response16:52 The backstory of building the IBDVerse atlas at scale20:29 How coding and non-coding IBD variants converge on the same genes and pathways23:38 The case for pathway-specific polygenic risk scores28:17 Building a longitudinal multi-omics dataset to predict IBD progression and drug response30:08 Why Sanger's next cohort targets sick and underrepresented patients rather than healthy volunteers34:07 What Carl looks for when interviewing PhD students and faculty candidates 39:20 A call to junior scientists and closing remarksFind out more:IBDverse study

This week on The Genetics Podcast, Patrick is joined by Dr. Pradeep Natarajan, Director of Preventive Cardiology at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. They discuss the discovery of clonal hematopoiesis as a driver of cardiovascular disease, the inflammatory mechanisms and emerging therapies targeting it, the growing clinical case for polygenic risk scores, and Pradeep's upcoming move to lead cardiometabolic and human genetics research at Amgen.Show Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Pradeep01:30 The origin story of clonal hematopoiesis (CH) as a cardiovascular risk factor 09:41 CH mutations such as TET2 that are linked to cardiovascular disease12:27 Evidence tying inflammation to CH and drugs that could target it16:49 TenSixteen Bio’s strategy for targeting CH and the challenge of finding the right patients21:33 Trajectory of CH across age and somatic mosaicism beyond blood26:44 How polygenic risk scores fill a gap in cardiovascular risk prediction34:49 The future clinical applications of polygenic risk scores39:20 The challenge of standardizing polygenic risk scores for clinical and regulatory use42:27 Pradeep's move to pharmaceutical company Amgen and his reasons for it46:23 Closing remarksFind out more:Clonal hematopoiesis paper

This week on The Genetics Podcast, Patrick is joined by Dr. Christopher Walsh, Professor of Pediatrics and Neurology at Harvard Medical School, Chief of Genetics and Genomics at Boston Children's Hospital, and HHMI Investigator. They discuss his path from neurobiology to human genetics, how somatic mosaicism in the brain drives disease from epilepsy to Alzheimer's, and what this reveals about new therapeutic targets for neurodegeneration.Show Notes0:00 Intro to The Genetics Podcast00:59 Welcome to Chris01:18 Chris’ path from neurobiology to human genetics04:55 How collaboration and mentorship have shaped Chris' career06:59 Somatic mosaicism and genetic mutations in the brain, from epilepsy to Alzheimer’s13:56 Repurposing cancer therapeutics and targeting DNA damage as new approaches to Alzheimer's15:29 A shared pattern of DNA damage across neurodegenerative diseases and the mechanism behind it19:36 How healthy neurons accumulate mutations with age and what that means for the brain23:21 How mutation rates and patterns vary across cell types26:23 How genome quality control and synaptic pruning may explain both brain development and neurodegeneration30:33 Why some people maintain a healthy brain into old age33:57 Chris’ advice for early-career scientists on pursuing goals36:43 Closing remarksFind out more:https://walshlab.org/