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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

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 Notes

0:00 Intro to The Genetics Podcast

00:58 Welcome to Carl

02:05 The origins of IBDVerse and mapping genetic effects on gene regulation across gut cell types in IBD

05:43 How anti-TNFs and newer genetically-supported IBD drugs have reshaped treatment 

08:04 Genetic versus environmental contributions to IBD

09:53 Using single-cell data to uncover IBD disease subtypes

13:22 Drug sequencing and immunogenicity in treatment response

16:52 The backstory of building the IBDVerse atlas at scale

20:29 How coding and non-coding IBD variants converge on the same genes and pathways

23:38 The case for pathway-specific polygenic risk scores

28:17 Building a longitudinal multi-omics dataset to predict IBD progression and drug response

30:08 Why Sanger's next cohort targets sick and underrepresented patients rather than healthy volunteers

34:07 What Carl looks for when interviewing PhD students and faculty candidates 

39:20 A call to junior scientists and closing remarks

Find 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 Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Pradeep

01:30 The origin story of clonal hematopoiesis (CH) as a cardiovascular risk factor 

09:41 CH mutations such as TET2 that are linked to cardiovascular disease

12:27 Evidence tying inflammation to CH and drugs that could target it

16:49 TenSixteen Bio’s strategy for targeting CH and the challenge of finding the right patients

21:33 Trajectory of CH across age and somatic mosaicism beyond blood

26:44 How polygenic risk scores fill a gap in cardiovascular risk prediction

34:49 The future clinical applications of polygenic risk scores

39:20 The challenge of standardizing polygenic risk scores for clinical and regulatory use

42:27 Pradeep's move to pharmaceutical company Amgen and his reasons for it

46:23 Closing remarks

Find 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 Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Chris

01:18 Chris’ path from neurobiology to human genetics

04:55 How collaboration and mentorship have shaped Chris' career

06:59 Somatic mosaicism and genetic mutations in the brain, from epilepsy to Alzheimer’s

13:56 Repurposing cancer therapeutics and targeting DNA damage as new approaches to Alzheimer's

15:29 A shared pattern of DNA damage across neurodegenerative diseases and the mechanism behind it

19:36 How healthy neurons accumulate mutations with age and what that means for the brain

23:21 How mutation rates and patterns vary across cell types

26:23 How genome quality control and synaptic pruning may explain both brain development and neurodegeneration

30:33 Why some people maintain a healthy brain into old age

33:57 Chris’ advice for early-career scientists on pursuing goals

36:43 Closing remarks

Find out more:

https://walshlab.org/

This week on The Genetics Podcast, Patrick is joined by Yentli Soto Albrecht, physician-scientist in training and founder of CureC9. They discuss how losing her father to C9orf72 ALS, and later learning her own genetic risk, reshaped the direction of her career. The conversation explores the biology linking the C9 repeat expansion to ALS and FTD, and how CureC9 is removing barriers across biomarkers, therapeutics, and patient samples to accelerate progress toward a cure.

Show Notes

0:00 Intro to The Genetics Podcast

00:58 Welcome to Yentli

02:34 How Yentli's father's C9 ALS diagnosis and her own genetic risk led her to pivot her research career toward curing it

06:41 The biology of the C9orf72 repeat expansion and how TDP-43 dysregulation links it to ALS and FTD

11:40 Therapeutic strategies targeting TDP-43 pathology in ALS and FTD

15:35 The state of biomarkers for ALS and FTD, and why C9-FTD trials lag behind ALS

22:08 How Yentli is lowering barriers for biomarker, cell line, and drug development through CureC9

30:40 Call for collaborators and where to follow Yentli 

32:59 Closing remarks

Find out more: CureC9

This week on The Genetics Podcast, we're re-airing our conversation with Eric Green, Founder and CEO of Trace Neuroscience, Co-Founder and Chief Scientific Officer at Maze Therapeutics, and Adjunct Clinical Assistant Professor at Stanford University School of Medicine. Patrick and Eric discuss Eric's transition from cardiology to entrepreneurship, the role of highly focused biotechs in creating precision therapies, and the development of high-impact gene therapies for people with amyotrophic lateral sclerosis (ALS). We're revisiting this episode following Trace Neuroscience's recent announcement that the first patient has been dosed with its antisense oligonucleotide (ASO) designed to restore UNC13A function in ALS.

Show Notes

0:00 Intro to The Genetics Podcast

02:03 Welcome to Eric, his background in cardiology, and how he got into biotech

06:23 Eric’s experience incubating and spinning out early-stage companies with Third Rock Ventures and developing Maze Therapeutics

09:13 Eric’s decision to transition from academia to the world of biotech

11:24 Building Maze Therapeutics and Eric’s focus on and genetic modifiers to discover new drugs   

15:09 The growth of therapeutic modalities in the context of genetics and gene therapies

16:48 What led Eric to launch Trace Neuroscience to develop ALS therapies

28:35 The process of getting Trace’s ALS therapies into the clinic

32:22 The identification of therapeutic value in low odds ratio genes

35:58 Eric’s view on the APOA1 gene target and its major effect size in kidney disease

40:03 How best to integrate genetics and genetic discovery into small and medium biotechs

41:50 Closing remarks

Find out more

• Trace Neuroscience

• https://www.businesswire.com/news/home/20260622451252/en/Trace-Neuroscience-Initiates-Global-Clinical-Development-Program-for-TRCN-1023-an-Antisense-Oligonucleotide-Designed-to-Restore-UNC13A-Function-for-the-Treatment-of-ALS

This week on The Genetics Podcast, Patrick is joined by Dr. Timothy Yu, Associate Professor of Pediatrics at Harvard Medical School and Physician/Researcher at Boston Children’s Hospital. They discuss how one child’s hidden genetic mutation led Tim into individualized ASO medicine, what it takes to develop n-of-1 therapies, and how new regulatory frameworks could expand treatment options for children with ultra-rare genetic disease.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Tim

02:05 How uncovering the genetic mutation underlying an ultra-rare disease led Tim into personalized ASO medicine

07:38 Challenges in developing a custom ASO 

12:25 How Tim’s team has scaled individualized ASO therapies to reach more than 50 patients worldwide

16:18 Measuring clinical benefit in n-of-1 therapies with natural history data, wearables, and biomarkers

20:24 How the N-of-1 Collaborative helps rare disease researchers share infrastructure 

24:28 Comparing ASOs, base editing, and prime editing for individualized rare disease therapies

30:06 Finding scalable models for n-of-1 therapies in newborn genetic disease

33:52 The potential impact of the FDA’s Plausible Mechanism framework on bespoke therapies

36:58 Connecting rapid newborn genome sequencing to earlier treatment for rare genetic disease

42:10 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Cara Altimus, CEO of BD², and Dr. Benjamin Neale, Associate Professor at Harvard Medical School and Massachusetts General Hospital. They discuss how rare variant discovery is opening new routes into bipolar disorder biology, how BD² is combining genetics with longitudinal multimodal data, and how patient priorities are shaping a research model focused on faster diagnosis and more precise treatments.

Show Notes

0:00 Intro to The Genetics Podcast

00:58 Welcome to Cara and Ben

01:57 The origin and aims of BD2 

04:20 Major knowledge gaps in bipolar disorder genetics

06:43 Using genetics and deep phenotyping to map bipolar disorder biology

13:47 Why bipolar disorder genetics needs both scale and deep clinical data

17:32 Finding the most predictive data for bipolar disorder biology and care

19:19 The search for scalable biomarkers in bipolar disorder

21:35 How BD² is building a bridge from discovery to clinical trials

26:48 Why bipolar diagnosis takes years and what patients want research to solve

33:08 How BD² is looking to other programs as inspiration to build a new research model

35:31 What overlapping risk genes reveal across bipolar disorder, schizophrenia, and autism

37:40 How rare variants could de-risk precision psychiatry trials

41:25 How BD² is scaling from early milestones to global funder momentum

45:04 Closing remarks 

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more:

• BD2
  

This week on The Genetics Podcast, Patrick is joined by Dr. Angela Bradshaw, Director for Research at Alzheimer Europe and honorary lecturer at the University of Glasgow. Following a series of recent episodes exploring Alzheimer’s disease research, we’re revisiting this conversation to bring in an essential patient advocacy and nonprofit perspective on the field. Patrick and Angela discuss how Alzheimer Europe partners in and supports pan-European dementia research, the heterogeneity of dementia and Alzheimer’s disease, the future of potential new gene therapies, and the critical role advocacy organizations play in ensuring research reflects the needs and priorities of patient communities.
Show Notes

0:00 Intro to The Genetics Podcast

01:27 Welcome to Angela and how she joined Alzheimer Europe

06:06 The biggest priorities and areas of focus for dementia and Alzheimer’s Disease (AD) research

10:10 Biomarkers for dementia and how early in disease development they can be utilized

12:40 The heterogeneity of dementia and AD and current understanding of subtypes and treatment journeys

17:20 The challenges of diagnosis, early identifiers, and the integration of genetics

18:53 Angela’s view on the latest breakthrough therapies

22:50 Partnering in and supporting dementia research efforts across 30+ European countries

29:15 Reimbursement frameworks and shared regulations across different countries

33:40 Angela’s thoughts on the near future of gene therapies for AD and dementia

38:04 Why Angela spent 50 hours travelling the length of Australia by bus

41:26 Closing remarks

Find out more

• Alzheimer Europe

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This week on The Genetics Podcast, Patrick is joined by Salvador Rico, Chief Medical Officer at Encoded Therapeutics. With Encoded’s Dravet syndrome gene therapy program recently reaching major clinical and regulatory milestones, we’re revisiting this conversation on Salvador’s journey into drug development, his work on gene therapy for X-linked myotubular myopathy, and the fundamental challenges and exciting advances shaping the future of genetic medicine.

Show Notes

0:00 Intro to The Genetics Podcast

01:27 Welcome to Salvador and how he became involved in drug development

11:29 Frustrations and rewards of the genetics field

14:27 Salvador’s study on gene therapy for patients with X-linked myotubular myopathy (XLMTM)

20:13 Risk of liver issues in gene therapy trials and attempts to mitigate them

24:50 Encoded Therapeutics‘ approach to drug discovery and what motivated Salvador to join the team

27:50 Steps towards therapeutic targeting of gene regulatory elements 

30:32 Advantages of different methods for drug delivery 

32:59 DNA- versus RNA-based therapy

35:24 Insights from approaches in other fields, including psychiatry

37:03 Considerations for using natural history studies

41:00 Expectations and goals for Encoded Therapeutics’ current and upcoming studies

43:45 Closing remarks

Find out more

• Encoded Therapeutics

• New clinical data

This week on The Genetics Podcast, Patrick is joined by Dr. Vincent Dion, Group Leader at the UK Dementia Research Institute at Cardiff University. They discuss how repeat expansions drive Huntington’s disease and other neurological disorders, why DNA repair can sometimes worsen these mutations over time, and how CRISPR nickase editing could offer a new way to shrink disease-causing repeats rather than simply silence them.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Vincent

01:45 Working on origins-of-life chemistry in Stanley Miller’s lab

03:56 Vincent’s path to genetics 

06:00 How somatic repeat expansion drives Huntington’s disease 

09:40 Therapeutic strategies for Huntington’s disease

15:29 Using gene editing to shrink repeat expansions

18:31 Optimizing CRISPR nickase delivery and expression for repeat expansion editing

25:15 Moving gene editing from academic research toward a first-in-human trial

27:31 Clinical trial challenges for Huntington’s gene therapies and uniQure’s early data

30:47 Epigenetic regulation of repeat instability in neurodegenerative disease

33:14 How basic science breakthroughs like CRISPR become transformative biology tools

34:55 How academic couples navigate the two-body problem when building research careers

39:39 Developing biomarkers to measure whether DNA-targeting therapies are working

42:17 Closing remarks

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This week on The Genetics Podcast, Patrick is joined by Dr. Paul Valdmanis, Associate Professor at the University of Washington. They discuss the impact of APOE4 on risk in Alzheimer’s disease, how long-read sequencing is uncovering hidden genetic variation in Alzheimer’s and ALS, and what rare variants and cryptic splicing can teach us about neurodegeneration.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Paul

01:40 Long-read sequencing and ancestry-specific APOE4 risk in Alzheimer’s disease

04:20 Key findings from Paul’s study on a protective APOE4-linked variant in Alzheimer’s disease

10:58 What rare PSEN1 and PSEN2 variants reveal about Alzheimer’s disease biology

14:38 Disease-specific genetic mechanisms in ALS versus Alzheimer’s

17:14 Precision therapies for neurodegenerative disease

18:35 Choosing therapeutic targets in the neurodegenerative disease cascade

20:21 Landscape of ALS and Alzheimer’s therapies 

23:48 Lessons from liver-directed gene therapy on microRNA toxicity, cancer risk, and brain delivery challenges

29:12 Using long-read sequencing to uncover tandem repeat expansions missed by conventional genomics

33:26 Findings from a study of long-read sequencing on ancient genomes

38:06 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more:

• APOE study

• Ancestry study
  

This week on The Genetics Podcast, Patrick is joined by Dr. Bin Yu, CDSS Chancellor’s Distinguished Professor at UC Berkeley. They discuss how different statistical approaches, from linear models to random forests, can be used to study complex genetic traits, recent findings on epistasis in cardiomyopathy, and how improving robustness and reproducibility can lead to more reliable scientific conclusions.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Bin

01:47 Linear models as the foundation of genetic analysis

05:34 Using random forests and stability to identify gene–gene interactions beyond linear models

11:05 How iterative feature weighting in random forests improves detection of gene interactions

13:10 Using GWAS to prioritize features in high-dimensional genetic data

15:06 Applying stable interaction models to hypertrophic cardiomyopathy in UK Biobank

20:47 Biological insights from gene–gene interactions in cardiomyopathy and evidence for indirect epistasis

23:25 Scaling discovery of epistatic interactions with better data and integrated experimental validation

27:21 The predictability, computability, and stability (PCS) framework for data science

30:06 How Bin’s early life during the Chinese Cultural Revolution shaped her 

32:54 Balancing AI-driven productivity with human reasoning and scientific thinking

35:23 Developing the ability to read people through observation, listening, and real-world interaction

38:03 Closing remarks

Find out more:

• Epistasis in cardiac hypertrophy study

• https://vdsbook.com/

This week on The Genetics Podcast, Patrick is joined by Dr. Sarah Marzi, Senior Lecturer at King's College London and group leader at the UK Dementia Research Institute. They discuss the impact of genes and environment on neurodegenerative disease, including: how APOE genotype shapes microglial function, how cell type-specific epigenomics of postmortem brain tissue is revealing the role of microglia and oligodendrocytes in Alzheimer's disease, and how pesticide exposure drives selective dopaminergic neuron loss and neuroinflammation in Parkinson's.

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Sarah

02:13 Environmental contributions to Parkinson’s disease and ALS

05:01 The role of microglia in Alzheimer’s disease and findings from a study on APOE variants in a mouse model

12:50 APOE4 effects on lipid accumulation, microglial activation, and vitamin D receptor signaling 

14:20 Building a multi-omic atlas of the Alzheimer’s brain

18:01 Overview of the pathological cascade of events in the Alzheimer’s brain

20:31 Anti-amyloid therapies, early intervention, and combination treatment strategies 

22:24 Rotenone exposure and microglial immune activation in Parkinson’s disease

29:24 Dopaminergic neuron vulnerability to pesticide exposure and mitochondrial dysfunction 

31:04 Familial Parkinson’s genes, polygenic Alzheimer’s risk, and genetically targeted clinical trials

33:13 Polygenic risk and microglial cell state regulation in Alzheimer’s disease

34:13 Defining cell states in single cell RNA sequencing

35:30 Oligodendrocyte epigenetic and transcriptional changes in Alzheimer’s disease

37:23 Sarah’s most memorable hiking adventures

38:58 Closing remarks

Find out more:

• Alzheimer’s APOE microglia xenotransplantation study

• Rotenone exposure Parkinson’s study

This week on The Genetics Podcast, Patrick is joined by Lindsey Wahlstrom, Co-Founder and Chief Momatologist of Rona’s FUN LAB, Jimi Olaghere, sickle cell disease patient advocate and early CRISPR gene therapy trial participant, and Rachel Smith, Vice President and Head of Rare and Genetic Diseases at Parexel. They discuss the realities of developing and delivering advanced therapies in rare disease, how funding models, regulation, and trial design shape access and outcomes, and why embedding patient experience early is critical to building therapies that are not only effective but scalable, accessible, and meaningful for patients and families.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to guests and what Rare Disease Day means to them

08:09 Balancing hope with funding, pricing, and access in advanced therapies

11:48 Why patient access must be built into drug development from day one

14:20 Patient engagement, community readiness, and the realities of trial participation

17:49 Why early patient input is still inconsistent and often treated as a checkbox

23:20 Designing trials around what actually matters to patients and families

26:53 Navigating regulators, payers, and trial design constraints in rare disease therapies

36:02 Redefining success in gene therapy around access, scalability, and real patient benefit

43:27 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Suzanne Schindler, Associate Professor of Neurology at Washington University in St. Louis. They discuss how blood-based biomarkers like p-tau217 are transforming our ability to detect and stage Alzheimer’s disease, how “clock models” can estimate when symptoms may begin, and how combining biomarkers with clinical phenotyping could improve trial design, prognosis, and patient care.

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Suzanne

01:35 Neurobiology of Alzheimer’s disease and how it differs from dementia

06:22 Presymptomatic changes to phosphorylated tau (p-tau) in the brain

07:36 The role of the APOE gene in Alzheimer’s

09:07 Differences in neuropathology in women vs men with Alzheimer’s

10:19 Rare cases where amyloid and tau pathology do not align in Alzheimer’s

12:37 Using plasma p-tau217 trajectories to estimate when Alzheimer’s symptoms may begin

17:30 Using p-tau217 to select clinical trial participants and predict progression timelines

20:59 Overview of therapeutic strategies in Alzheimer’s disease

24:24 Why APOE effects may not appear in p-tau217 measurements

26:30 Combining biomarkers and clinical phenotyping to understand disease progression in Alzheimer’s

30:08 Early-onset vs late-onset Alzheimer’s and differences in clinical presentation

31:45 Expanding beyond p-tau217 to proteomics and multimodal biomarkers for predicting symptoms

33:52 MTBR-tau243 as a more specific marker of tau pathology and Alzheimer’s symptoms

37:31 Expanding biomarkers beyond Alzheimer’s and bringing blood tests into clinical practice

38:49 Closing remarks

Find out more:

• Phosphorylated tau217 study

• MTBR-tau243 study
  

This week on The Genetics Podcast, Patrick is joined by Derek Ansel, Global Vice President and Therapeutic Strategy Lead for Rare Disease and Oncology at Worldwide Clinical Trials. They discuss how contract research organizations design and run rare disease trials, the challenges of selecting endpoints and patient populations, and how emerging approaches like n-of-1 therapies, regulatory flexibility, and AI are reshaping clinical development.
Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Derek

01:38 The role of Contract Research Organizations (CROs) in clinical development

02:41 Why endpoints are the hardest problem in rare disease trial design

05:24 How Derek’s team chooses and operationalizes endpoints in rare disease trials

08:14 Balancing patient selection, signal detection, and trial feasibility in rare disease

11:55 How the FDA’s new guidance for personalized therapies could accelerate rare disease drug development

14:20 Patient engagement, genetic counseling, and decision-making in genetic trials

19:30 Patient and clinician dynamics in genetic subtypes of common disease

23:05 What needs to change to make n-of-1 therapies scalable and accessible

26:12 Where AI is delivering real impact in clinical trials today and where it is heading

31:24 Operational bottlenecks, risk tolerance, and the limits of AI adoption in clinical trials

34:55 Derek’s path from early clinical research roles to genetic counseling and rare disease drug development

38:51 Key areas driving progress in rare disease over the next five years

41:42 Closing remarks

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This week on The Genetics Podcast, Patrick is joined by Dr. Tim Jobson, consultant physician and gastroenterologist at Somerset NHS Foundation Trust and Medical Director of Predictive Health Intelligence (PHI). They discuss the rising burden of metabolic liver disease and how routine clinical data can be used to detect disease earlier and prevent late-stage presentation. They also discuss the LiveWell study, a collaboration between Sano Genetics and PHI, and what it reveals about layering genetics and other data types to improve risk stratification and clinical trial recruitment. 

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Tim

01:50 The rise of metabolic liver disease and worsening mortality trends

04:35 Motivation and goals behind the Somerset Liver Improvement Program to address late diagnosis

09:13 Where genetics is already used in liver disease and where it’s still emerging

13:17 Current tools for staging liver disease and the challenge of predicting progression at scale

18:48 How the LiveWell study could improve risk prediction and reshape trial recruitment in liver disease

23:58 Applying longitudinal risk detection beyond liver disease to cardiometabolic and other chronic conditions

26:35 Using subtle changes in routine blood tests to identify cancer risk earlier

28:09 Using existing health data to drive earlier intervention and maximize patient impact

30:05 Expanding beyond liver disease, scaling early detection, and advancing precision medicine

32:18 Closing remarks

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This week on The Genetics Podcast, Patrick is joined by Dr. Glenn Cohen, Professor at Harvard Law School. They discuss the evolving legal and ethical landscape of reproductive genetics, why regulation in areas like embryo selection remains limited, and questions arising around the use of AI in healthcare.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Glenn

01:35 An overview of the courses Glenn teaches at Harvard Law School

02:29 Glenn’s areas of expertise across biomedical ethics

03:20 Ethical considerations around reproductive medicine and polygenic risk scores

10:37 Regulatory uncertainty and limited oversight in reproductive genetics

13:18 Liability, regulation, and real-world implementation challenges for AI in healthcare

14:52 Risk–benefit framework for evaluating AI use in clinical settings

17:19 Glenn’s experience contributing to landmark Supreme Court cases in biotechnology and health law

20:09 Glenn’s perspective on mitochondrial replacement and its regulatory divide between the UK and US

22:20 Closing remarks

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This week on The Genetics Podcast, Patrick is joined by Dr. Andrea Ganna, Associate Professor at the Institute for Molecular Medicine Finland (FIMM). They discuss the promise and limits of polygenic risk scores for disease prediction and clinical trials, how large-scale electronic health records and AI models could transform medical research and healthcare planning, what Finland’s national health data infrastructure enables for population-scale studies, and how genetics can be used to strengthen trial emulation in observational data.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Andrea

01:51 Andrea’s research focuses, including polygenic scores in biobanks and AI applications 

03:02 Complementarity between polygenic scores and electronic health record–derived risk signals across biobanks

04:47 Using polygenic risk scores for prognostic versus predictive enrichment in clinical trials

10:28 Limitations and opportunities of using AI models on large-scale electronic health records

15:47 Legal, data infrastructure, and privacy barriers to building AI models on health records

18:04 Choosing model architectures for healthcare AI 

19:47 Using AI and multi-omics data to integrate biological knowledge and the challenge of learning causality

21:43 How removing genetic effects from proteins improves disease prediction and highlights the role of environment

24:42 Finland’s health data ecosystem and national biobanks

28:11 Using genetics to improve trial emulation in biobank data and observational studies

33:42 Closing remarks

Find out more:

• Trial emulation study

• Polygenic scores study

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This week on The Genetics Podcast, Patrick is joined by Dr. Anna Lindstrand, Professor and Consultant in Clinical Genetics and Genomics at the Karolinska Institute. They discuss how Sweden has scaled whole genome sequencing as a first-line test for rare disease, what long-read sequencing adds to clinical diagnostics, how national genomic infrastructure can accelerate translation into precision medicine, and where prevention and adult genomic screening may fit into the future of healthcare.

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Anna

01:34 Choosing between whole genome, exome, panels, and long-read sequencing in clinical practice

04:05 Evaluating long-read sequencing in the clinic 

06:37 What long-read sequencing adds to diagnostic yield

09:15 The role of RNA sequencing, proteomics, and methylation profiling as complementary tools in clinical genomics

13:07 Building a coordinated national infrastructure for clinical genomics and rare disease research in Sweden

18:20 The shift toward precision therapeutics and new standards for clinical actionability

23:18 Using national genomic data and registries to make Sweden trial-ready for precision therapies

27:01 Moving beyond monogenic models to capture polygenic and borderline signals in clinical genomics

30:44 Genomics for prevention including adult screening and pharmacogenomics

36:23 Anna’s research priorities for the next phase of genomic medicine and structural variant discovery

38:32 Closing remarks

Find out more:

• Long-read sequencing study

• Moving beyond monogenic disease paper

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This week on The Genetics Podcast, Patrick is joined by Dr. Matthew Goldstein, CEO of jscreen. They discuss his journey from physician-scientist and biotech founder to leading a national nonprofit focused on preventive genetic screening, how a personal tragedy reshaped his mission around carrier screening and access, and what it will take to close the gap between the promise of genomics and its real-world implementation in healthcare.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:58 Welcome to Matthew

01:41 Matthew’s path from an MD-PhD to founding a personalized cancer vaccine biotech

09:06 From personal tragedy to leading jscreen to expand access to reproductive carrier screening 

17:11 Purpose, grief, and how Matthew has led jscreen in honor of his daughter

20:38 The implementation gap between genomic potential and real-world preventive screening 

23:33 Nonprofit models, reimbursement barriers, and building sustainable access to preventive genetic screening

28:27 Lessons from the Jewish community’s experience with Tay-Sachs and gaps in understanding

33:05 Preconception carrier screening and the role of community in preventive health

38:04 Closing remarks

Find out more: jscreen

This week on The Genetics Podcast, Patrick is joined by Dr. Ryan Dhindsa, Assistant Professor at the Baylor College of Medicine and PI at Texas Children’s Hospital, and Dr. Caleb Lareau, PI at Memorial Sloan Kettering Cancer Center and Assistant Professor of Computational Biology and Medicine at Weill Cornell Medicine. They discuss how a Twitter DM sparked a multi-year collaboration to extract Epstein–Barr virus signals from large-scale human genomic datasets, how measuring viral persistence in UK Biobank data reveals insights into autoimmune disease risk and host genetic control, and what this work means for understanding the long-term impact of chronic viral infections on human health.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Ryan and Caleb

01:58 How a Twitter DM led to a long-term collaboration

03:10 Rescuing Epstein–Barr virus (EBV) sequences from human whole genome data 

04:45 Quantifying EBV persistence in UK Biobank, validating the signal, and uncovering links to autoimmune disease

12:00 Computational virology, chronic viral effects on human disease, and extending the approach to the broader human virome

16:59 Design considerations for population genomics programs to better capture chronic viral effects on human disease

21:30 Genetic, viral strain, and environmental factors that shape EBV persistence and immune control

26:09 Future directions for EBV research and expanding beyond European ancestry cohorts

29:46 Focus areas of Ryan’s research including rare variant genetics, neurological disease mechanisms, and pediatric population genomics

33:49 Focus areas of Caleb’s research including the human virome and expanding sequencing technologies to detect uncharacterized nucleic acids

37:03 Where genomic “dark matter” may underlie unexplained cancer and severe disease

38:46 Gaps in non-coding variant interpretation and incomplete penetrance in unsolved genetic disease

42:01 Closing remarks

Find out more:

• Ryan’s research group

• Caleb’s research group
  

This week on The Genetics Podcast, Patrick is joined by Dr. Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at the Big Data Institute, University of Oxford. They discuss the discovery of a new neurodevelopmental syndrome caused by mutations in the small nuclear RNA gene RNU4-2, what this reveals about the non-coding genome and the spliceosome, and how large-scale genome sequencing is reshaping diagnosis, variant interpretation, and the future of genetic medicine.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Nicky

02:09 Overview of the non-coding genome and its functional elements

03:59 How small nuclear RNAs drive splicing and exon recognition

04:54 Overview of the major and minor spliceosomes and the role of small nuclear RNAs in intron removal

06:34 Discovery of recurrent de novo RNU4-2 mutations in developmental disorders through large-scale genomics data

12:18 Growth of patient advocacy groups and global networks following the discovery of ReNU syndrome

14:43 Potential for antisense oligonucleotide therapies for ReNU syndrome

16:06 Clinical endpoints, treatment timing, and biomarker development for ReNU

18:32 Impact of RNU4-2 discovery on exome design, genome sequencing adoption, and targeted testing strategies

19:52 Distinct dominant, recessive, and retinal phenotypes arising from variants within RNU4-2

22:15 Open questions on mutation rates and selection in spliceosomal small nuclear RNAs

25:25  Limits of non-coding variant discovery and the unresolved genetic burden in developmental disorders

29:52 Therapeutic upregulation strategies targeting untranslated regions in haploinsufficiency 

33:40 The MRC Centre of Research Excellence in Therapeutic Genomics’ approach to scalable genetic medicines

35:54 Long-term prospects and delivery challenges for gene editing approaches 

36:56 Newborn genome screening, actionability debates, and implications for rare disease diagnosis

40:25 Population genomics insights from unascertained newborn genome sequencing cohorts

42:04 Closing remarks

Find out more: ReNU discovery paper

This week on The Genetics Podcast, Patrick is joined by Dr. David Dismuke, Chief Technical Officer at Forge Biologics, and Dr. Steven Gray, Professor at UT Southwestern Medical Center. They discuss the evolution of AAV gene therapy from academic labs to industrial-scale manufacturing, how vector design and capsid engineering are improving CNS delivery, and what manufacturing innovation and next-generation delivery technologies mean for safety, cost, and the future of gene therapy.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to David and Steven

01:47 David and Steven’s overlapping academic paths and long-term collaboration

03:39 Steven’s research on AAV engineering for central nervous system (CNS) gene therapy

04:50 Forge Biologics’ platform approach to scalable AAV manufacturing

06:28 How AAV vectors are manufactured

08:24 How CNS AAV vectors are designed, tested, and refined across programs

10:58 How manufacturing quality and trial outcomes can shape AAV development decisions

15:13 Factors that impact the ratio of full versus empty AAV capsids

17:21 Manufacturing scale, capsid efficiency, and the future cost curve of AAV gene therapy

24:19 Scaling AAV manufacturing for common diseases and the shift toward industrialized production models

27:07 Engineered AAV capsids for CNS delivery and the tradeoffs between innovation and platform stability

30:31 Next-generation AAV delivery and gene editing technologies

34:41 Lessons from Jude Samulski on translating AAV science into real-world therapies

37:21 Closing remarks

Find out more: Forge Biologics

This week on The Genetics Podcast, Patrick is joined by Daniel Chung, Chief Medical Officer of Beacon Therapeutics. They discuss lessons from developing the first ocular gene therapy (Luxturna), the complexities of designing and executing pivotal trials in inherited retinal disease, and how endpoint selection, delivery, and immunogenicity shape clinical and commercial success.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Daniel

01:57 Daniel’s firsthand experience with the development and approval of Luxturna for inherited retinal dystrophy

06:13 Factors contributing to delays in approval for gene therapies in recent years 

08:13 Overview of ocular diseases and their suitability for gene therapy

11:40 Why Daniel joined Beacon Therapeutics and current priorities for the lead program

13:22 Key challenges in designing and executing a pivotal gene therapy trial for X-linked retinitis pigmentosa (XLRP)

15:49 Lessons from prior inherited retinal disease trials and selecting the right clinical endpoints

21:03 Expanding beyond the lead program into earlier patients and additional ocular indications

23:43 AAV packaging constraints and managing immunogenicity in ocular gene therapy

26:29 Lessons from academia–industry collaboration in developing gene therapies

28:23 Access to genetic testing in inherited retinal diseases and remaining gaps

32:10 Key scientific, regulatory, and commercial challenges facing gene therapy today

35:39 Closing remarks

Find out more:

• Beacon Therapeutics

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This week on The Genetics Podcast, Patrick is joined by Zornitza Stark, Professor at the University of Melbourne and Co-Group Leader at the Murdoch Children’s Research Institute. Using early findings from the BabyScreen+ genomic newborn screening study, they examine feasibility, clinical impact, and family-wide implications beyond standard screening, and consider what these insights mean for infrastructure, policy, and equitable implementation at scale.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to Zornitza

01:55 Methods and findings of the BabyScreen+ study 

04:35 Scaling the BabyScreen+ study from pilot to population screening

07:46 Balancing benefits, risks, and downstream implications in genomic newborn screening

15:55 How the genes tested in BabyScreen+ were selected

19:00 Cascade testing and the family-wide implications of genomic newborn screening

22:05 What large-scale genomic newborn screening could reveal about penetrance 

23:57 Expanding genomic newborn screening over time and addressing equity, scale, and long-term value

27:47 Rapid genomic sequencing in critically ill newborns from pilot studies to national implementation

34:32 Building evidence infrastructure to interpret variants and support reimbursement decisions

37:25 Why global data sharing in genomics requires policy alignment and sustained infrastructure investment

39:55 Current priorities and the future direction of genomics in Australia

42:14 Closing remarks

Find out more:

• BabyScreen+ study

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This week on The Genetics Podcast, Patrick is joined for a special recording at the Flagship Pioneering studio during JPM 2026 by Michelle Werner, CEO of Alltrna, and Mike Severino, CEO of Tessera Therapeutics. They discuss the molecular mechanisms behind Alltrna’s engineered tRNA and Tessera’s gene-writing platforms, why 2026 marks a major inflection point as both programs enter the clinic, and considerations around trial design, patient needs, and delivering therapies at scale.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Michelle and Mike

01:26 Overview of Alltrna’s therapeutic approach to rare genetic diseases using engineered tRNAs

03:19 Overview of Tessera Therapeutics’ gene writing approach

04:51 Preclinical evidence supporting first-in-human testing of Alltrna’s lead candidate

07:50 Why Tessera’s preclinical models are predictive of clinical success

10:40 Key features that differentiate Tessera’s RNA-based gene writing

14:02 Advantages of using basket trials for engineered tRNAs

18:00 Clinical trial design and early efficacy signals for gene writing in alpha-1 antitrypsin deficiency

21:59 Genetic testing, patient identification, and patient advocacy in Alltrna trials

24:18 Differentiating Tessera’s gene writing approach for patients and investigators

26:35 Site readiness and expertise required for genetic medicine trials

28:32 Scaling Alltrna’s platform across mutations, tissues, and diseases

32:34 Expanding Tessera’s gene writing platform beyond alpha-1 antitrypsin deficiency

35:57 Perspectives on biotech funding, pharma partnerships, and rare disease investment

39:08 The data pharma looks for when partnering on novel genetic therapies

42:49 Emerging technologies Michelle and Mike are watching beyond their own platforms 

47:19 Closing remarks

Find out more:

• Alltrna (https://www.alltrna.com/)

• Tessera Therapeutics (https://www.tesseratherapeutics.com/)

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Dr. Travis Hinson, Professor and physician at the University of Connecticut and investigator at the Jackson Laboratory. They discuss how genetics is reshaping the understanding of heart failure, why sarcomere biology has become a central target for new gene-based therapies, and how advances in genome editing and preventive genetics could redefine cardiovascular care.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to Travis

01:44 Overview of gene editing for inherited cardiovascular disease

05:01 Delivery methods and viral capsid engineering to target heart tissue

07:29 Role of the titin gene in dilated cardiomyopathy and treatment opportunities

10:32 Genetic variants in titin and differences in phenotype

13:51 Promising therapeutic approaches for targeting titin 

16:21 Possibility of using a mini titin gene for replacement

17:31 Sarcomere proteins and their role in cardiomyopathy

20:28 Limits of current understanding in heart failure, including cardiac regeneration and congenital heart disease

24:50 Predicting drug-induced cardiotoxicity using stem cell models, animal studies, and digital twins

30:02 How Travis balances clinical genetics at the University of Connecticut with translational research at the Jackson Laboratory (JAX)

32:03 Where genetic testing is used in cardiology today and what’s limiting broader access

35:19 Understanding polygenic risk and unexplained heritability in cardiovascular disease

37:07 Managing inherited cardiomyopathy risk in families after a pathogenic variant is identified

40:36 Genetic testing as a prevention strategy and the public health case for earlier intervention

43:03 Balancing early genetic screening with penetrance, uncertainty, and patient anxiety

45:51 Closing remarks

Find out more:

Review on cardiovascular gene editing approaches

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This week on The Genetics Podcast, Patrick is joined by Dr. Beth Shapiro, Chief Science Officer at Colossal Biosciences. They discuss her path into ancient DNA and evolutionary genetics, how advances in genome engineering are reshaping de-extinction and conservation science, and why restoring lost ecological functions could transform the future of biodiversity.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Beth

01:43 Beth’s path from journalism to ancient DNA research

04:46 Beth’s first project on American bison and near extinction

08:26 How Beth worked on a dodo sample at Oxford and what ancient DNA could reveal

11:09 How de-extinction entered the field and why resurrecting species became a scientific goal

14:54 Why de-extinction efforts could strengthen ecosystems and accelerate species conservation

18:33 How cloning a mammoth works and why genome engineering replaces traditional cloning

25:05 Understanding the genome of a woolly mammoth

28:06 What functional de-extinction means in practice

30:55 Genetic clues behind the woolly mammoth’s coat

33:25 The technical hurdles behind de-extinction

38:23 Building a stepwise path to de-extinction through near-term conservation tools

39:36 Ethics risk management and working with local and Indigenous communities in de-extinction projects

44:59 Scientific and technological breakthroughs needed over the next decade to make de-extinction and biodiversity preservation viable

49:20 Closing remarks

Find out more:

Colossal Biosciences (https://colossal.com/)

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Dr. Graham Dempsey, CEO and co-founder of Quiver Bioscience. They discuss Graham’s path into neuroscience and biotech, how Quiver is building genetically validated programs in pain and neurodevelopmental disorders, and what recent advances in RNA-based therapies could mean for the future of neurological disease.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Graham

01:29 The motivations and mission driving Quiver Bioscience

04:34 Quiver’s approach to targeting the brain for neurological disease

06:58 Nav1.7 as a lead pain program and the mechanisms of pain signaling

12:11 Patient population and unmet need in chronic pain 

13:37 The Dup15q neurodevelopmental program and recent clinical progress

17:29 How the company chooses which diseases to pursue and why genetically validated pain and epilepsy programs lead the pipeline

20:10 Modeling pain in a dish and how cellular electrophysiology reveals disease and drug effects

27:42 Lessons from building a biotech company

29:53 Today’s biotech climate and why Graham is optimistic 

31:56 Emerging delivery technologies that could unlock the next wave of oligonucleotide therapies

33:51 How molecular shuttles cross the blood–brain barrier and the advantage of a dual target approach

37:05 Graham’s path from aspiring sports medicine doctor to building light-based platforms in neuroscience

40:15 Graham’s early exposure to biotech leadership and a formative encounter with Roy Vagelos

42:09 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

Find out more:

• Quiver Bioscience (https://www.quiverbioscience.com/)

This week on The Genetics Podcast, Patrick is joined by Dr. Arabella Bouzigues, Coordinator of the Genetic Frontotemporal Dementia Initiative (GENFI) and postdoctoral researcher. They discuss the scale and structure of GENFI as a global collaboration and what longitudinal data is revealing about genetics and biomarkers in frontotemporal dementia.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to Arabella 

01:30 Background and structure of the Genetic Frontotemporal Initiative (GENFI) consortium

02:48 Scale of the GENFI cohort and the breadth of longitudinal data collected

06:06 Clinical signs and progression of frontotemporal dementia (FTD) 

10:08 How genetic variants map onto different clinical forms of frontotemporal dementia

12:11 Biomarkers in genetic FTD and the challenge of separating neurodegeneration from lifelong brain differences

19:36 Mutation-specific cortical microstructure patterns in FTD and what MRI reveals at the earliest stages

23:04 Why combining genetics imaging fluid and digital biomarkers is essential for early detection and trials in FTD

25:39 How the GENFI consortium is run across more than 50 sites worldwide

30:42 How urgency and unmet need drive strong collaboration in the FTD community

33:11 Promising developments in FTD therapeutics

36:39 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more: 

• GENFI (https://www.genfi.org/)

This week on The Genetics Podcast, Patrick is joined by Dr. Krishna Aragam, Section Head of Cardiovascular Genomics and Precision Medicine at the Cleveland Clinic. They discuss Krishna’s early experiences in population research and how they shaped his approach to genetics, the major discoveries transforming cardiovascular genomics from monogenic to polygenic risk, and how new insights into heart failure and population-specific variants are redefining the future of clinical care.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Krishna 

01:40 How a gap year in India deepened Krishna’s interest in health and population genomics

06:16 Key advances that reshaped cardiovascular genomics from rare variants to polygenic risk

09:18 Where cardiovascular genomics stands today across coronary disease, cardiomyopathies, and arrhythmias

14:25 Factors that make heart failure challenging for genomics 

17:32 How monogenic variants and polygenic load shape risk in dilated cardiomyopathy

23:03 What genetics reveals about the roots of heart failure and why precise phenotypes matter

26:12 Using genetic risk to guide earlier treatment and prevent progression to heart failure

30:37 Subclinical markers and imaging strategies to track progression toward heart failure

32:04 Key research findings on an ancestry-specific genetic driver of dilated cardiomyopathy

41:21 Genetic signals highlighting the role of inflammation in coronary artery disease

43:11 Building a clinical genomics engine that connects discovery to cardiovascular care

47:14 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more: 

• Genetic variants underlying DCM: https://pmc.ncbi.nlm.nih.gov/articles/PMC11631752/

•  Ancestry-specific CD36 study: https://www.nature.com/articles/s41588-025-02372-2
  

Summary: 

This week on The Genetics Podcast, Patrick is joined by Lisa Gurry, Chief Business Officer of GeneDx. They discuss her path from two decades at Microsoft to leading one of the most influential genomics companies, GeneDx’s mission to deliver the fastest rare disease diagnoses, and how large-scale data, newborn screening, and AI are shaping the future of precision medicine.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to Lisa and her career path leading to joining GeneDx  

03:27 The core components of GeneDx and how they drive early rare disease diagnosis

06:18 Insights from early genomic newborn screening pilots

11:37 The clinical impact and economic benefits of newborn genomic screening

14:27 How GeneDx combines data, AI, and clinical expertise to improve genomic interpretation

17:44 A vision for a lifelong genomic passport and how it could guide care across every stage of life

20:42 How GeneDx Infinity is unlocking new therapeutic possibilities in genetically linked autism

22:48 How advocacy communities guide patient identification and connect families to opportunities

26:00 Lessons from 23 years at Microsoft that Lisa now applies to leading GeneDx

30:39 How Truveta emerged from the COVID crisis to build a shared-data platform for population-scale health insights

32:13 What excites Lisa most about leading GeneDx and where she sees the biggest opportunities ahead

34:59 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

 This week on The Genetics Podcast, Patrick is joined by Dr. Jeffrey Chamberlain, Professor at the University of Washington School of Medicine, co-founder of Kinea Bio, and Director of the Muscular Dystrophy Cooperative Research Center of Seattle. They discuss the early breakthroughs that revealed the structure and function of the dystrophin gene, how those insights led to the creation of micro-dystrophin and systemic AAV delivery in Duchenne, and the major scientific and clinical challenges the field must now solve.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Jeffrey

01:33 Early discovery of the dystrophin gene and how it shaped Duchenne muscular dystrophy (DMD) research

09:07 Efforts to map dystrophin and develop practical diagnostic techniques

12:04 How research in Jeffrey’s lab gradually led to the creation of micro-dystrophin 

20:15 How micro-dystrophin and AAV delivery converged into a viable systemic gene therapy strategy

27:23 Current successes and safety challenges in systemic AAV gene therapy for neuromuscular disease

34:44 Prospects and limitations of gene editing for Duchenne and emerging alternatives to AAV micro-dystrophin

44:57 Closing remarks

Please consider rating and reviewing us on your chosen podcast listening platform! 

https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Summary: 

This week on The Genetics Podcast, Patrick is joined by Dr. Rachel Salzman, CEO of Armatus Bio. They discuss the promise of vectorized RNAi for autosomal dominant diseases, the key scientific and clinical hurdles in gene therapy, and Rachel’s lessons from two decades in the field.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to Rachel

01:35 Background of Armatus Bio and the mechanism behind its vectorized RNAi platform

05:31 Advantages of vectorized RNAi over conventional RNAi approaches

08:07 How microRNAs work and how engineered versions enable highly specific gene silencing

10:28 Current preclinical progress at Armatus and next steps toward first-in-human trials

14:06 Lessons on making smart risk decisions in rare disease drug development

17:26 Reflections on two decades of progress, setbacks, and realities in gene therapy

22:07 Hemophilia as a case study in gene therapy missteps and overlooked patient and market realities

25:21 Challenges around product purity and the need for financial innovation

29:23 Why AAV purity is so difficult to achieve and where pre-competitive collaboration could drive improvement

33:32 Rachel’s path from veterinary medicine to gene therapy through a family genetic diagnosis

35:58 Founding the Stop ALD Foundation and advancing lentiviral gene therapy into first-in-human use

39:58 The future potential of vectorized RNAi 

42:00 Closing remarks

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Summary: 

This week on The Genetics Podcast, Patrick is joined by Slavé Petrovski, Vice President of the Center for Genomics Research at AstraZeneca. They discuss how AstraZeneca is scaling population genomics through massive biobank collaborations, developing AI models for early disease prediction, and pioneering sustainable “green” algorithms to reduce the environmental footprint of large-scale genomic research.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Slavé

02:09 Slavé’s career path from business information systems to genomics

04:33 How Slavé decided to move from academia to industry

07:52 Scaling and diversifying biobank partnerships to unlock new genetic insights

12:29 Translating biobank data into predictive and preventive medicine

15:14 Discovering protective genetic variants through global biobank studies

19:13 Leveraging population genetics to identify and validate protective drug targets

23:52 Developing an AI tool (MILTON) for integrating multi-omic and clinical data for early disease prediction

28:12 Redefining clinical trials in a presymptomatic and predictive medicine era

30:49 AstraZeneca’s efforts to make large-scale genomics computing sustainable through green algorithm innovation

39:05 AstraZeneca’s open science strategy and global impact of its shared genomics tools

42:10 Fostering critical thinking and avoiding groupthink in large-scale genomics research

45:30 Looking ahead to the next decade of genomics and precision healthcare

50:01 Closing remarks

Find out more

• MILTON (https://www.astrazeneca.com/r-d/our-technologies/machine-learning-drug-discovery.html)

• PheWAS Portal (https://azphewas.com/)

• Upcoming webcast with deep dive into MILTON & PheWAS (https://www.nature.com/articles/d44224-025-00033-7)

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This week on The Genetics Podcast, Patrick is joined by Dr. Ellen Reisinger, Professor and group leader at the University of Tübingen. They discuss her journey into hearing loss research, why otoferlin has become a leading target for gene therapy, and the emerging science shaping the next generation of treatments.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Ellen

01:52 Ellen’s career path that coincidentally led to her work on otoferlin-related hearing loss

03:22 Mechanism and advantages of the dual adenoassociated virus (AAV) system 

05:35 The genetic landscape of early-onset hearing loss and why otoferlin stands out

07:42 Why otoferlin-related deafness is an ideal target for postnatal gene therapy development

09:53 Potential next gene therapy targets beyond otoferlin and associated challenges

13:13 Carrier and newborn screening as approaches to preventing hereditary hearing loss

14:37 How far the field is from prenatal gene therapy and why it remains unlikely in the near term

16:07 Exploring gene-agnostic and protective approaches to prevent or slow hearing loss

18:22 How genetics and environment interact in age-related hearing loss

20:00 Current research focus of Ellen’s group on degenerative hearing loss genes and uncovering cell death mechanisms

22:05 Using mouse models and human organoids to study hearing loss mechanisms

23:42 Emerging gene editing approaches 

25:20 Ellen’s research journey from biochemistry to leading gene therapy research in hearing loss 

27:54 Unanswered questions about how inner hair cells release neurotransmitters

29:21 Comparing outcomes of gene therapy and cochlear implants for hearing restoration and differences across languages

34:20 Closing remarks

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Summary: 

This week on The Genetics Podcast, Patrick is joined by BridgeBio’s Ananth Sridhar, Chief Operating Officer of Cardiorenal Programs, and Sun-Gou Ji, Vice President of Computational Genomics. They discuss the hub-and-spoke model for de-risking and accelerating rare disease drug development, the role of human genetics in target discovery, lessons from their autosomal dominant hypocalcemia type 1 (ADH1) program, and how portfolio design and predictive genomics are shaping the future of precision medicine.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Ananth & Sun-Gou

01:57 How BridgeBio’s hub-and-spoke model de-risks and accelerates rare disease drug development

06:45 How programs move from the hub to the spokes in target discovery and development

09:10 Translating a target into a therapy for autosomal dominant hypocalcemia type 1 (ADH1)

12:28 Challenges in ADH1 drug development and using population genetics to identify patients with gain-of-function variants

18:08 Under-diagnosis and incomplete penetrance in rare disease and quantifying genetic versus phenotypic prevalence

20:52 Balancing first-in-class innovation with risk management in rare disease drug development

24:24 Evaluating rare disease programs using risk-adjusted net present value (NPV) instead of peak sales

27:20 Key factors that can make rare disease programs faster and cheaper to develop, and why modality agnosticism is important

32:00 Sun-Gou’s experience in computational genetics and building data-driven infrastructure for discovery

36:44 Ananth’s lessons from Regeneron and applying patient-centered principles to rare disease drug development

39:00 Sun-Gou on the power of newborn sequencing and personal lessons from early diagnosis

43:36 Ananth’s views on making predictive medicine more personal and human-centered

44:51 Closing remarks

Find out more

• BridgeBio (https://bridgebio.com/unlocking-rare-diseases-medicine)

• Hub-and-spoke model (https://www.youtube.com/watch?v=gRURL49QsX4)

• ADH1 publication (https://www.cell.com/ajhg/fulltext/S0002-9297(25)00244-7)

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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Summary: 

This week on The Genetics Podcast, Patrick is joined by Justin Porcano, co-founder and Executive Director of Save Sight Now. They discuss how his daughter’s diagnosis with Usher syndrome type 1B (USH1B) inspired the founding of Save Sight Now, the organization’s efforts to accelerate research and overcome barriers in gene therapy, and the innovative gene delivery methods and therapeutic approaches currently in development.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Justin

01:39 How Justin’s daughter’s Usher syndrome diagnosis (USH1B) led to the founding of Safe Sight Now and a mission to accelerate research

05:23 Biggest hurdles to therapeutic development for USH1B

08:36 Progress in the research with new animal models and advances in clinical endpoint development

10:25 How Justin applied design thinking and AI to rapidly learn rare disease science

12:38 Advances in gene delivery approaches for USH1B

15:45 Therapeutic intervention windows in USH1B with early treatment for hearing loss and later options for addressing vestibular and visual impairments

18:32 Save Sight Now’s plans for the next phase of clinical translation and sustainable growth

20:50 Why Justin decided to establish Save Sight Now as an independent nonprofit

22:27 The need for stronger collaboration between patient organizations and biotech companies

25:50 Building global collaborations to expand Save Sight Now’s reach

28:00 How the community can support Save Sight Now’s mission and upcoming fundraising gala

28:59 Closing remarks

Find out more

• Save Sight Now (https://www.savesightnow.org/)

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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Summary: 

This week on The Genetics Podcast, recorded live at ASHG 2025, Patrick is joined by Heidi Rehm, Chief Genomics Officer at MGH’s Center for Genomic Medicine and Co-director at the Broad Institute, and Slavé Petrovski, Vice President of AstraZeneca's Centre for Genomics Research. They discuss the rapid progress of large-scale genomics, the barriers to integrating genetic data into healthcare and drug development, and how open collaboration, global data sharing, and a focus on equity are driving more inclusive and impactful genomic discovery.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Heidi and Slavé

02:01 Slavé’s role at AstraZeneca and work in genomics-driven R&D 

03:24 Heidi’s work at the Broad Institute bridging clinical genomics, rare disease research, and global data-sharing initiatives

04:12 Heidi on breaking a Guinness world record for rapid neonatal ICU (NICU) genomics and the shift to open data sharing

06:32 Slavé on how large-scale, multimodal human data is transforming genomics research

08:10 Heidi’s initiatives to integrate genomics into routine care at hospitals and with primary care physicians

11:47 Integrating genomics into clinical trials and healthcare, and enabling global discovery through AstraZeneca’s open data portal

15:34 Breaking down legal and logistical barriers to genomic data sharing and centering the patient voice

18:40 AstraZeneca’s large-scale plasma proteome study and machine learning models predicting disease onset years before diagnosis

21:44 Emerging omics tools advancing rare disease diagnosis

24:19 The value and pitfalls of AI in genomics today

28:54 Advancing health equity in genomics through data sharing, diverse recruitment, and global collaboration

33:40 Progress and challenges in next-generation genetic therapies

37:15 Reflections and advice for the next generation entering genomics and data-driven medicine

40:44 Audience Q&A

51:44 Closing remarks

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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link