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

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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