EP 220: Turning human brain physiology into RNA medicines with Graham Dempsey of Quiver Bioscience

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)

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